Online First Article

Volume 8 (2017)

Number 1 / March 2017

 

     Page 34

Richard J.E. Skipworth, James A. Ross

Ken Fearonno abstract

 

Skipworth, R. J. E., and Ross, J. A. (2017) Ken Fearon. Journal of Cachexia, Sarcopenia and Muscle, 8: 3–4. doi: 10.1002/jcsm.12187.

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     Page 518

Marta Gonzalez-Freire, Richard D. Semba, Ceereena Ubaida-Mohien, Elisa Fabbri, Paul Scalzo, Kurt Højlund, Craig Dufresne, Alexey Lyashkov, Luigi Ferrucci

The Human Skeletal Muscle Proteome Project: a reappraisal of the current literatureSkeletal muscle is a large organ that accounts for up to half the total mass of the human body. A progressive decline in muscle mass and strength occurs with ageing and in some individuals configures the syndrome of ‘sarcopenia’, a condition that impairs mobility, challenges autonomy, and is a risk factor for mortality. The mechanisms leading to sarcopenia as well as myopathies are still little understood. The Human Skeletal Muscle Proteome Project was initiated with the aim to characterize muscle proteins and how they change with ageing and disease. We conducted an extensive review of the literature and analysed publically available protein databases. A systematic search of peer-reviewed studies was performed using PubMed. Search terms included ‘human’, ‘skeletal muscle’, ‘proteome’, ‘proteomic(s)’, and ‘mass spectrometry’, ‘liquid chromatography-mass spectrometry (LC-MS/MS)’. A catalogue of 5431 non-redundant muscle proteins identified by mass spectrometry-based proteomics from 38 peer-reviewed scientific publications from 2002 to November 2015 was created. We also developed a nosology system for the classification of muscle proteins based on localization and function. Such inventory of proteins should serve as a useful background reference for future research on changes in muscle proteome assessed by quantitative mass spectrometry-based proteomic approaches that occur with ageing and diseases. This classification and compilation of the human skeletal muscle proteome can be used for the identification and quantification of proteins in skeletal muscle to discover new mechanisms for sarcopenia and specific muscle diseases that can be targeted for the prevention and treatment.

 

Gonzalez-Freire, M., Semba, R. D., Ubaida-Mohien, C., Fabbri, E., Scalzo, P., Højlund, K., Dufresne, C., Lyashkov, A., and Ferrucci, L. (2017) The Human Skeletal Muscle Proteome Project: a reappraisal of the current literature. Journal of Cachexia, Sarcopenia and Muscle, 8: 5–18. doi: 10.1002/jcsm.12121.

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     Page 1924

Amirhossein Sahebka, Nikou Saboni, Matteo Pirro, Maciej Banach

Curcumin: An effective adjunct in patients with statin-associated muscle symptoms?In spite of the unequivocal efficacy of statins in reducing primary and secondary cardiovascular events, the use of these drugs in a considerable number of patients is limited because of statin intolerance, mainly statin-associated muscle symptoms (SAMS). SAMS encompass a broad spectrum of clinical presentations, including mild muscular aching and other types of myalgias, myopathy with the significant elevation of creatine kinase, and the rare but life-threatening rhabdomyolysis. Among several pathophysiologic mechanisms of SAMS, mitochondrial dysfunction is thought to be one of the main one. Curcumin is the polyphenolic ingredient of Curcuma longa L., which has various pharmacological properties against a vast range of diseases. Curcumin has several mechanisms of actions relevant to the treatment of SAMS. These effects include the capacity to prevent and reduce delayed onset muscle soreness by blocking the nuclear factor inflammatory pathway, attenuation of muscular atrophy, enhancement of muscle fibre regeneration following injury, and analgesic and antioxidant effects. Curcumin can also increase the levels of cyclic adenosine monophosphate, which leads to an increase in the number of mitochondrial DNA duplicates in skeletal muscle cells. Finally, owing to its essential lipid-modifying properties, curcumin might serve as an adjunct to statin therapy in patients with SAMS, allowing for effective lowering of low-density lipoprotein cholesterol and possibly for statin dose reduction. Owing to the paucity of effective treatments, and the safety of curcumin in clinical practice, proof-of-concept trials are recommended to assess the potential benefit of this phytochemical in the treatment of SAMS.

 

Sahebkar, A., Saboni, N., Pirro, M., and Banach, M. (2017) Curcumin: An effective adjunct in patients with statin-associated muscle symptoms?. Journal of Cachexia, Sarcopenia and Muscle, 8: 19–24. doi: 10.1002/jcsm.12140.

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     Page 2539

Mochamat, Henning Cuhls, Milka Marinova, Stein Kaasa, Christiane Stieber, Rupert Conrad, Lukas Radbruch, Martin Mücke

A systematic review on the role of vitamins, minerals, proteins, and other supplements for the treatment of cachexia in cancer: a European Palliative Care Research Centre cachexia projectWe provide a systematic review to support the European Palliative Care Research Collaboration development of clinical guidelines for cancer patients suffering from cachexia. CENTRAL, MEDLINE, PsycINFO, ClinicalTrials.gov, and a selection of cancer journals have been searched up until 15 April 2016. The systematic literature research yielded 4214 publications with 21 of these included in the final evaluation. Regarding minerals, our search identified only one study examining the use of magnesium with no effect on weight loss. As far as vitamins are concerned, vitamin E in combination with omega-3 fatty acids displayed an effect on survival in a single study, vitamin D showed improvement of muscle weakness in prostate cancer patients, and vitamin C supplementation led to an improvement of various quality of life aspects in a sample with a variety of cancer diagnoses. For proteins, a combination therapy of β-hydroxy-β-methylbutyrate (HMB), arginine, and glutamine showed an increase in lean body mass after 4 weeks in a study of advanced solid tumour patients, whereas the same combination did not show a benefit on lean body mass in a large sample of advanced lung and other cancer patients after 8 weeks. L-carnitine led to an increase of body mass index and an increase in overall survival in advanced pancreatic cancer patients. Adverse effects of food supplementation were rare and showed mild intensity. There is not enough solid evidence for the use of minerals, vitamins, proteins, or other supplements in cancer. No serious adverse effects have been reported with dietary supplementation.

 

Mochamat, , Cuhls, H., Marinova, M., Kaasa, S., Stieber, C., Conrad, R., Radbruch, L., and Mücke, M. (2017) A systematic review on the role of vitamins, minerals, proteins, and other supplements for the treatment of cachexia in cancer: a European Palliative Care Research Centre cachexia project. Journal of Cachexia, Sarcopenia and Muscle, 8: 25–39. doi: 10.1002/jcsm.12127.

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     Page 4047

Alessio Molfino, Alessandro Iannace, Maria Chiara Colaiacomo, Alessio Farcomeni, Alessandra Emiliani, Gianfranco Gualdi, Alessandro Laviano, Filippo Rossi Fanelli

Cancer anorexia: hypothalamic activity and its association with inflammation and appetite-regulating peptides in lung cancerBackground
Energy homeostasis is mediated by the hypothalamus, whose inflammation-induced functional derangements contribute to the onset of anorexia in cancer. By using functional magnetic resonance imaging (fMRI), we determined the patterns of hypothalamic activation after oral intake in anorexic (A), non-anorexic (NA) cancer patients, and in controls (C).
Methods
Lung cancer patients were considered. Hypothalamic activation was recorded in A and NA patients and in C by fMRI, before (T0), immediately after (T1) the administration of an oral nutritional supplement, and after 15?min (T2). The grey of the hypothalamus and Blood Oxygen Level Dependent (BOLD) intensity were calculated and normalized for basal conditions. Interleukin (IL)-1, IL-6, tumour necrosis factor (TNF)-a, ghrelin, and leptin plasma levels were measured. A statistical parametric mapping was used.
Results
Thirteen lung cancer patients (7?M, 6?F; 9A, 4NA) and 2 C (1?M, 1?F) were enrolled. Controls had the lowest BOLD intensity. At all-time points, anorexic patients showed lower hypothalamic activity compared with NA (P?<?0.001) (T0: 585.57?±?55.69 vs. 667.92?±?33.18, respectively; T1: 536.50?±?61.70 vs. 624.49?±?55.51, respectively; T2: 556.44?±?58.51 vs. 615.43?±?71.50, respectively). Anorexic patients showed greater BOLD signal reduction during T0–T1 than NA (-8.5% vs. -6.80%, P?<?0.001). Independently from the presence of anorexia, BOLD signals modification before and after oral challenge correlated with basal values of IL-1 and ghrelin (P?<?0.001).
Conclusions
Hypothalamic activity in A cancer patients is reduced respect to NA and responds differently to oral challenges. This suggests a central control of appetite dysregulation during cancer anorexia, before, and after oral intake.

 

Molfino, A., Iannace, A., Colaiacomo, M. C., Farcomeni, A., Emiliani, A., Gualdi, G., Laviano, A., and Rossi Fanelli, F. (2017) Cancer anorexia: hypothalamic activity and its association with inflammation and appetite-regulating peptides in lung cancer. Journal of Cachexia, Sarcopenia and Muscle, 8: 40–47. doi: 10.1002/jcsm.12156.

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     Page 4856

Oskar Wendowski, Zoe Redshaw, Gabriel Mutungi

Dihydrotestosterone treatment rescues the decline in protein synthesis as a result of sarcopenia in isolated mouse skeletal muscle fibresBackground
Sarcopenia, the progressive decline in skeletal muscle mass and function with age, is a debilitating condition. It leads to inactivity, falls, and loss of independence. Despite this, its cause(s) and the underlying mechanism(s) are still poorly understood.
Methods
In this study, small skeletal muscle fibre bundles isolated from the extensor digitorum longus (a fast-twitch muscle) and the soleus (a slow-twitch muscle) of adult mice of different ages (range 100–900 days old) were used to investigate the effects of ageing and dihydrotestosterone (DHT) treatment on protein synthesis as well as the expression and function of two amino acid transporters; the sodium-coupled neutral amino acid transporter (SNAT) 2, and the sodium-independent L-type amino-acid transporter (LAT) 2.
Results
At all ages investigated, protein synthesis was always higher in the slow-twitch than in the fast-twitch muscle fibres and decreased with age in both fibre types. However, the decline was greater in the fast-twitch than in the slow-twitch fibres and was accompanied by a reduction in the expression of SNAT2 and LAT2 at the protein level. Again, the decrease in the expression of the amino acid transporters was greater in the fast-twitch than in the slow-twitch fibres. In contrast, ageing had no effect on SNAT2 and LAT2 expressions at the mRNA level. Treating the muscle fibre bundles with physiological concentrations (~2 nM) of DHT for 1 h completely reversed the effects of ageing on protein synthesis and the expression of SNAT2 and LAT2 protein in both fibre types.
Conclusion
From the observations that ageing is accompanied by a reduction in protein synthesis and transporter expression and that these effects are reversed by DHT treatment, we conclude that sarcopenia arises from an age-dependent reduction in protein synthesis caused, in part, by the lack of or by the low bioavailability of the male sex steroid, DHT.

 

Wendowski, O., Redshaw, Z., and Mutungi, G. (2017) Dihydrotestosterone treatment rescues the decline in protein synthesis as a result of sarcopenia in isolated mouse skeletal muscle fibres. Journal of Cachexia, Sarcopenia and Muscle, 8: 48–56. doi: 10.1002/jcsm.12122.

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     Page 5768

Piyawan Kittiskulnam, Juan J. Carrero, Glenn M. Chertow, George A. Kaysen, Cynthia Delgado, Kirsten L. Johansen

Sarcopenia among patients receiving hemodialysis: weighing the evidenceBackground
There is no consensus on how best to define low muscle mass in patients with end-stage renal disease. Use of muscle mass normalized to height-squared has been suggested by geriatric societies but may underestimate sarcopenia, particularly in the setting of excess adiposity. We compared four definitions of low muscle mass in a prevalent hemodialysis cohort.
Methods
ACTIVE/ADIPOSE enrolled prevalent patients receiving hemodialysis from the San Francisco and Atlanta areas from June 2009 to August 2011. Whole-body muscle mass was estimated using bioelectrical impedance spectroscopy, performed before a midweek dialysis session (n = 645; age 56.7 ± 14.5 years, 41% women). We defined low muscle mass as muscle mass of 2SD or more below sex-specific bioelectrical impedance spectroscopy-derived means for young adults (18–49 years) from National Health and Nutrition Examination Survey and indexed to height2, body weight (percentage), body surface area (BSA) by the DuBois formula, or Quételet's body mass index (BMI). We compared prevalence of low muscle mass among the four methods and assessed their correlation with strength and physical performance.
Results
The prevalence of low muscle mass ranged from 8 to 32%. Muscle mass indexed to height2 classified the smallest percentage of patients as having low muscle mass, particularly among women, whereas indexing by BSA classified the largest percentage. Low muscle mass/height2 was present almost exclusively among normal or underweight patients, whereas indexing to body weight and BMI classified more overweight and obese patients as having low muscle mass. Handgrip strength was lower among those with low muscle mass by all methods except height2. Handgrip strength was directly and modestly correlated with muscle mass normalized by percentage of body weight, BSA, and BMI (ρ = 0.43, 0.56, and, 0.64, respectively) and less so with muscle/height2 (ρ = 0.31, P  < 0.001). The difference in grip strength among patients with low vs. normal muscle mass was largest according to muscle/BMI (−6.84 kg, 95% CI −8.66 to −5.02, P < 0.001). There were significant direct correlations of gait speed with muscle mass indexed to percentage of body weight, BSA, and BMI but not with muscle mass indexed to height2.
Conclusions
Skeletal muscle mass normalized to height2 may underestimate the prevalence of low muscle mass, particularly among overweight and obese patients on hemodialysis. Valid detection of sarcopenia among obese patients receiving hemodialysis requires adjustment for body size.

 

Kittiskulnam, P., Carrero, J. J., Chertow, G. M., Kaysen, G. A., Delgado, C., and Johansen, K. L. (2017) Sarcopenia among patients receiving hemodialysis: weighing the evidence. Journal of Cachexia, Sarcopenia and Muscle, 8: 57–68. doi: 10.1002/jcsm.12130.

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     Page 6977

Riccardo Calvani, Federico Marini, Matteo Cesari, Thomas W. Buford, Todd M. Manini, Marco Pahor, Christiaan Leeuwenburgh, Roberto Bernabei, Francesco Landi, Emanuele Marzetti

Systemic inflammation, body composition, and physical performance in old community-dwellersBackground
Chronic inflammation, changes in body composition, and declining physical function are hallmarks of the ageing process. The aim of the present study was to provide a preliminary characterisation of the relationship among these age-related phenomena via multivariate modelling.
Methods
Thirty-five old adults (OAs) and 17 young adults (YAs) were enrolled. The volume of skeletal muscle, subcutaneous adipose tissue (SAT), and intermuscular adipose tissue (IMAT) of the thigh was quantified by three-dimensional magnetic resonance imaging. Muscle strength was measured by knee extension strength testing. In OAs, physical performance was further assessed via the Short Physical Performance Battery (SPPB). Multi-block partial least squares-discriminant analysis (PLS-DA) was employed to explore the relationship among inflammatory profiles and functional and imaging parameters. Double cross-validation procedures were used to validate the predictive ability of the PLS-DA model.
Results
The optimal complexity of the PLS-DA model was found to be two latent variables. The proportion of correct classification was 92.3% in calibration (94.1% in YAs and 91.4% in OAs), 84.6% in internal validation (95.3% in YAs and 78.5% in OAs), and 82.6% in external validation (94% in YAs and 76.9% in OAs). Relative to YAs, OAs were characterised by smaller muscle volume, greater IMAT volume, lower muscle strength, and higher levels of myeloperoxidase, P-selectin, soluble intercellular adhesion molecule 1, and vascular cell adhesion molecule 1. Compared with OAs with SPPB >8, those scoring ≤8 were characterised by smaller muscle volume, greater SAT volume, lower muscle strength, and higher levels of interleukin 1 beta, 6, 10, 12, 13, tumour necrosis factor alpha, and granulocyte-macrophage colony-stimulating factor.
Conclusions
Multi-block PLS-DA identified distinct patterns of relationships among circulating cytokines and functional and imaging parameters in persons of different ages and varying levels of physical performance. The longitudinal implementation of such an innovative strategy could allow for the tracking of health status over time, the early detection of deviations in health trajectories, and the monitoring of response to treatments.

 

Calvani, R., Marini, F., Cesari, M., Buford, T. W., Manini, T. M., Pahor, M., Leeuwenburgh, C., Bernabei, R., Landi, F., and Marzetti, E. (2017) Systemic inflammation, body composition, and physical performance in old community-dwellers. Journal of Cachexia, Sarcopenia and Muscle, 8: 69–77. doi: 10.1002/jcsm.12134.

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     Page 7888

Ding-Cheng (Derrick) Chan, Hsiao-Hui Tsou, Chirn-Bin Chang, Rong-Sen Yang, Jau-Yih Tsauo, Ching-Yu Chen, Chin-Fu Hsiao, Ya-Ting Hsu, Chia-Hui Chen, Shu-Fang Chang, Chao Agnes Hsiung, Ken N. Kuo

Integrated care for geriatric frailty and sarcopenia: a randomized control trialBackground
Exercise, nutrition, and psychological interventions may all have positive impacts on frailty and sarcopenia. However, it is not known whether an integrated care programme with all three components can be beneficial and the intensity of such programme is also not certain. In this study, we aim to determine the effectiveness of two levels of integrated care on frailty and sarcopenia.
Methods
A randomized control trial was conducted at two community hospitals in Taiwan. Older adults (65–79 years of age, N  = 289) who scored ≥1 on the Cardiovascular Health Study Phenotypic Classification of Frailty (CHS_PCF) were enrolled in the trial. Low-level care (LLC) participants received a 2 h education course on frailty, sarcopenia, coping strategy, nutrition, and demonstration of study exercise programme. Educational multimedia material was distributed as reference for home practice with bi-monthly telephone follow-ups on adherences. High-level care (HLC) participants, in addition to LLC instructions, received six sessions of on-site problem solving therapy and 48 exercise sessions within 6 months. Brief nutrition consultation was also provided during the exercise sessions. Primary outcome was improvement of the CHS_PCF by at least one category (from pre-frail to robust, or from frail to pre-frail or robust) from baseline. Secondary outcomes included changes of individual frailty, and sarcopenia indicators. Assessments were done at 3, 6, and 12 months by trained research assistants blinded to randomization status. Intention-to-treat analysis was applied.
Results
Mean age was 71.6 ± 4.3 years, with 53% females. For the entire cohort, improvement of primary outcome was 35% at 3 months, increased to 40% at 6 months, and remained stable at 39% at 12 months. Improvement rates were similar in both groups. Compared with the LLC group, HLC participants had greater improvements in the following indices: energy expenditure of walking, 5 m walking time, dominant hand grip strength, timed-up-and-go-test, and one-leg-stand time — mainly at 6 and 12 month assessments.
Conclusions
The 6 month integrated care improved frailty and sarcopenia status among community-dwelling elders, with high-intensity training yielding greater improvements. Low-level care could be promoted as a basic intervention, while HLC could be reserved for those at high risk and with high motivation.

Chan, D.-C. (D)., Tsou, H.-H., Chang, C.-B., Yang, R.-S., Tsauo, J.-Y., Chen, C.-Y., Hsiao, C.-F., Hsu, Y.-T., Chen, C.-H., Chang, S.-F., Hsiung, C. A., and Kuo, K. N. (2017) Integrated care for geriatric frailty and sarcopenia: a randomized control trial. Journal of Cachexia, Sarcopenia and Muscle, 8: 78–88. doi: 10.1002/jcsm.12132.

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     Page 89101

Chloë Goossens, Mirna Bastos Marques, Sarah Derde, Sarah Vander Perre, Thomas Dufour, Steven E. Thiessen, Fabian Güiza, Thomas Janssens, Greet Hermans, Ilse Vanhorebeek, Katrien De Bock, Greet Van den Berghe, Lies Langouche

Premorbid obesity, but not nutrition, prevents critical illness-induced muscle wasting and weaknessBackground
The ‘obesity paradox’ of critical illness refers to better survival with a higher body mass index. We hypothesized that fat mobilized from excess adipose tissue during critical illness provides energy more efficiently than exogenous macronutrients and could prevent lean tissue wasting.
Methods
In lean and premorbidly obese mice, the effect of 5 days of sepsis-induced critical illness on body weight and composition, muscle wasting, and weakness was assessed, each with fasting and parenteral feeding. Also, in lean and overweight/obese prolonged critically ill patients, markers of muscle wasting and weakness were compared.
Results
In mice, sepsis reduced body weight similarly in the lean and obese, but in the obese with more fat loss and less loss of muscle mass, better preservation of myofibre size and muscle force, and less loss of ectopic lipids, irrespective of administered feeding. These differences between lean and obese septic mice coincided with signs of more effective hepatic fatty acid and glycerol metabolism, and ketogenesis in the obese. Also in humans, better preservation of myofibre size and muscle strength was observed in overweight/obese compared with lean prolonged critically ill patients.
Conclusions
During critical illness premorbid obesity, but not nutrition, optimized utilization of stored lipids and attenuated muscle wasting and weakness.

 

Goossens, C., Marques, M. B., Derde, S., Vander Perre, S., Dufour, T., Thiessen, S. E., Güiza, F., Janssens, T., Hermans, G., Vanhorebeek, I., De Bock, K., Van den Berghe, G., and Langouche, L. (2017) Premorbid obesity, but not nutrition, prevents critical illness-induced muscle wasting and weakness. Journal of Cachexia, Sarcopenia and Muscle, 8: 89–101. doi: 10.1002/jcsm.12131.

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     Page 102112

Ada S. Cheung, Hans Gray, Anthony G. Schache, Rudolf Hoermann, Daryl Lim Joon, Jeffrey D. Zajac, Marcus G. Pandy, Mathis Grossmann

Androgen deprivation causes selective deficits in the biomechanical leg muscle function of men during walking: a prospective case–control studyMethods
We conducted a 12-month prospective, observational case–control study of 34 men newly commencing androgen deprivation treatment (ADT) for prostate cancer and 29 age-matched prostate cancer controls. Participants were assessed at 0, 6, and 12 months while walking in a biomechanics laboratory. We combined video-based motion capture and ground reaction force data with computerized musculoskeletal modelling to assess the following primary outcomes: (i) peak joint torques at the hip, knee and ankle, and corresponding individual muscle forces; (ii) individual muscle contributions to acceleration of the body's centre of mass; and (iii) walking speed, stride length, and step width. A linear mixed model was used to compare mean differences between groups.
Results
Compared with controls over 12 months, men receiving ADT had a mean reduction in total testosterone level from 14.1 to 0.4 nmol/L, and demonstrated more marked decreases in peak hip flexor torque by 14% [mean difference −0.11 N/kg (−0.19, −0.03), P = 0.01] and peak knee extensor torque by 16% [−0.11 N/kg (−0.20, −0.02), P = 0.02] of the initial mean value. Correspondingly, iliopsoas force decreased by 14% (P = 0.006), and quadriceps force decreased by 11%, although this narrowly missed statistical significance (P = 0.07). Soleus decreased contribution to forward acceleration of the body's centre of mass by 17% [mean difference −0.17 m/s2 (−0.29, −0.05), P < 0.01]. No significant changes between groups were observed in other joint torques or individual muscle contributions to acceleration of the body. Step width increased by 18% [mean adjusted difference 1.4 cm (0.6, 27.4), P = 0.042] in the ADT group compared with controls, with no change in stride length or walking speed.
Conclusions
Testosterone deprivation selectively decreases lower-limb muscle function, predominantly affecting muscles that support body weight, accelerate the body forwards during walking, and mediate balance. Future exercise and pro-myogenic interventional studies to mitigate ADT-associated sarcopenia should target these deficits.

 

 

Cheung, A. S., Gray, H., Schache, A. G., Hoermann, R., Lim Joon, D., Zajac, J. D., Pandy, M. G., and Grossmann, M. (2017) Androgen deprivation causes selective deficits in the biomechanical leg muscle function of men during walking: a prospective case–control study. Journal of Cachexia, Sarcopenia and Muscle, 8: 102–112. doi: 10.1002/jcsm.12133.

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     Page 113121

Maria Kalafateli, Konstantinos Mantzoukis, Yan Choi Yau, Ali O. Mohammad, Simran Arora, Susana Rodrigues, Marie de Vos, Kassiani Papadimitriou, Douglas Thorburn, James O'Beirne, David Patch, Massimo Pinzani, Marsha Y. Morgan, Banwari Agarwal, Dominic Yu, Andrew K. Burroughs, Emmanuel A. Tsochatzis

Malnutrition and sarcopenia predict post-liver transplantation outcomes independently of the Model for End-stage Liver Disease scoreBackground
Although malnutrition and sarcopenia are prevalent in cirrhosis, their impact on outcomes following liver transplantation is not well documented.
Methods
The associations of nutritional status and sarcopenia with post-transplant infections, requirement for mechanical ventilation, intensive care (ICU) and hospital stay, and 1 year mortality were assessed in 232 consecutive transplant recipients. Nutritional status and sarcopenia were assessed using the Royal Free Hospital-Global Assessment (RFH-GA) tool and the L3-psoas muscle index (L3-PMI) on CT, respectively.
Results
A wide range of RFH-SGA and L3-PMI were observed within similar Model for End-stage Liver Disease (MELD) sub-categories. Malnutrition and sarcopenia were independent predictors of all outcomes. Post-transplant infections were associated with MELD (OR = 1.055, 95%CI = 1.002–1.11) and severe malnutrition (OR = 6.55, 95%CI = 1.99–21.5); ventilation > 24 h with MELD (OR = 1.1, 95%CI = 1.036–1.168), severe malnutrition (OR = 8.5, 95%CI = 1.48–48.87) and suboptimal donor liver (OR = 2.326, 95%CI = 1.056–5.12); ICU stay > 5 days, with age (OR = 1.054, 95%CI = 1.004–1.106), MELD (OR = 1.137, 95%CI = 1.057–1.223) and severe malnutrition (OR = 7.46, 95%CI = 1.57–35.43); hospital stay > 20 days with male sex (OR = 2.107, 95%CI = 1.004–4.419) and L3-PMI (OR = 0.996, 95%CI = 0.994–0.999); 1 year mortality with L3-PMI (OR = 0.996, 95%CI = 0.992–0.999). Patients at the lowest L3-PMI receiving suboptimal grafts had longer ICU/hospital stay and higher incidence of infections.
Conclusions
Malnutrition and sarcopenia are associated with early post-liver transplant morbidity/mortality. Allocation indices do not include nutritional status and may jeopardize outcomes in nutritionally compromised individuals.

 

Kalafateli, M., Mantzoukis, K., Choi Yau, Y., Mohammad, A. O., Arora, S., Rodrigues, S., de Vos, M., Papadimitriou, K., Thorburn, D., O'Beirne, J., Patch, D., Pinzani, M., Morgan, M. Y., Agarwal, B., Yu, D., Burroughs, A. K., and Tsochatzis, E. A. (2017) Malnutrition and sarcopenia predict post-liver transplantation outcomes independently of the Model for End-stage Liver Disease score. Journal of Cachexia, Sarcopenia and Muscle, 8: 113–121. doi: 10.1002/jcsm.12095.

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     Page 122130

Neil Johns, Cynthia Stretch, Benjamin H.L. Tan, Tora S. Solheim, Sveinung Sørhaug, Nathan A. Stephens, Ioannis Gioulbasanis, Richard J.E. Skipworth, D.A. Christopher Deans, Antonio Vigano, James A. Ross, Oliver F. Bathe, Michel L. Tremblay, Stein Kaasa, Florian Strasser, Bruno Gagnon, Vickie E. Baracos, Sambasivarao Damaraju1, Kenneth C.H. Fearon

New genetic signatures associated with cancer cachexia as defined by low skeletal muscle index and weight lossBackground
Cachexia affects the majority with advanced cancer. Based on current demographic and clinical factors, it is not possible to predict who will develop cachexia or not. Such variation may, in part, be due to genotype. It has recently been proposed to extend the diagnostic criteria for cachexia to include a direct measure of low skeletal muscle index (LSMI) in addition to weight loss (WL). We aimed to explore our panel of candidate single nucleotide polymorphism (SNPs) for association with WL +/− computerized tomography-defined LSMI. We also explored whether the transcription in muscle of identified genes was altered according to such cachexia phenotype
Methods
A retrospective cohort study design was used. Analysis explored associations of candidate SNPs with WL (n = 1276) and WL + LSMI (n = 943). Human muscle transcriptome (n = 134) was analysed using an Agilent platform.
Results
Single nucleotide polymorphisms in the following genes showed association with WL alone: GCKR, LEPR, SELP, ACVR2B, TLR4, FOXO3, IGF1, CPN1, APOE, FOXO1, and GHRL. SNPs in LEPR, ACVR2B, TNF, and ACE were associated with concurrent WL + LSMI. There was concordance between muscle-specific expression for ACVR2B, FOXO1 and 3, LEPR, GCKR, and TLR4 genes and LSMI and/or WL (P < 0.05).
Conclusions
The rs1799964 in the TNF gene and rs4291 in the ACE gene are new associations when the definition of cachexia is based on a combination of WL and LSMI. These findings focus attention on pro-inflammatory cytokines and the renin–angiotensin system as biomarkers/mediators of muscle wasting in cachexia.

 

Johns, N., Stretch, C., Tan, B. H. L., Solheim, T. S., Sørhaug, S., Stephens, N. A., Gioulbasanis, I., Skipworth, R. J. E., Deans, D. A. C., Vigano, A., Ross, J. A., Bathe, O. F., Tremblay, M. L., Kaasa, S., Strasser, F., Gagnon, B., Baracos, V. E., Damaraju, S., and Fearon, K. C. H. (2017) New genetic signatures associated with cancer cachexia as defined by low skeletal muscle index and weight loss. Journal of Cachexia, Sarcopenia and Muscle, 8: 122–130. doi: 10.1002/jcsm.12138.

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     Page 131144

Daniela Verzola, Alice Bonanni, Antonella Sofia, Fabrizio Montecucco, Elena D'Amato, Valeria Cademartori, Emanuele Luigi Parodi, Francesca Viazzi, Chiara Venturelli, Giuliano Brunori, Giacomo Garibotto

Toll-like receptor 4 signalling mediates inflammation in skeletal muscle of patients with chronic kidney diseaseBackground
Inflammation in skeletal muscle is implicated in the pathogenesis of insulin resistance and cachexia but why uremia up-regulates pro-inflammatory cytokines is unknown. Toll-like receptors (TLRs) regulate locally the innate immune responses, but it is unknown whether in chronic kidney disease (CKD) TLR4 muscle signalling is altered. The aim of the study is to investigate whether in CKD muscle, TLRs had abnormal function and may be involved in transcription of pro-inflammatory cytokine.
Methods
TLR4, phospho-p65, phospho-ikBα, tumour necrosis factor (TNF)-α, phospho p38, Murf 1, and atrogin were studied in skeletal muscle from nondiabetic CKD stage 5 patients (n = 29) and controls (n = 14) by immunohistochemistry, western blot, and RT–PCR. Muscle cell cultures (C2C12) exposed to uremic serum were employed to study TLR4 expression (western blot and RT–PCR) and TLR-driven signalling. TLR4 signalling was abrogated by a small molecule chemical inhibitor or TLR4 siRNA. Phospho AKT and phospho p38 were evaluated by western blot.
Results
CKD subjects had elevated TLR4 gene and protein expression. Also expression of NFkB, p38 MAPK and the NFkB-regulated gene TNF-α was increased. At multivariate analysis, TLR4 protein content was predicted by eGFR and Subjective Global Assessment, suggesting that the progressive decline in renal function and wasting mediate TLR4 activation. In C2C12, uremic serum increased TLR4 as well as TNF-α and down-regulated pAkt. These effects were prevented by blockade of TLR4.
Conclusions
CKD promotes muscle inflammation through an up-regulation of TLR4, which may activate downward inflammatory signals such as TNF-α and NFkB-regulated genes.

 

Verzola, D., Bonanni, A., Sofia, A., Montecucco, F., D'Amato, E., Cademartori, V., Parodi, E. L., Viazzi, F., Venturelli, C., Brunori, G., and Garibotto, G. (2017) Toll-like receptor 4 signalling mediates inflammation in skeletal muscle of patients with chronic kidney disease. Journal of Cachexia, Sarcopenia and Muscle, 8: 131–144. doi: 10.1002/jcsm.12129.

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     Page 145160

Abstracts of the 3rd International Conference on Cancer Cachexia, September 23–25, 2016 in Washington, DC, USAAbstracts of the 3rd International Conference on Cancer Cachexia, September 23–25, 2016 in Washington, DC, USAAbstracts of the 3rd International Conference on Cancer Cachexia, September 23–25, 2016 in Washington, DC, USA

 

(2017) Abstracts of the 3rd International Conference on Cancer Cachexia, September 23–25, 2016 in Washington, DC, USA. Journal of Cachexia, Sarcopenia and Muscle, 8: 145–160. doi: 10.1002/jcsm.12186.

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     Page 161183

Abstracts of the 9th International Conference on Cachexia, Sarcopenia, and Muscle Wasting, Berlin, Germany, 10–11 December 2016 (part 2)
Abstracts of the 9th International Conference on Cachexia, Sarcopenia, and Muscle Wasting, Berlin, Germany, 10–11 December 2016 (part 2)
Abstracts of the 9th International Conference on Cachexia, Sarcopenia, and Muscle Wasting, Berlin, Germany, 10–11 December 2016 (part 2)

(2017) Abstracts of the 9th International Conference on Cachexia, Sarcopenia, and Muscle Wasting, Berlin, Germany, 10–11 December 2016 (part 2). Journal of Cachexia, Sarcopenia and Muscle, 8: 161–183. doi: 10.1002/jcsm.12182.

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Number 2 / April 2017

 

     Page 187189

Maria Cristina Gonzalez, Steven B. Heymsfield

Bioelectrical impedance analysis for diagnosing sarcopenia and cachexia: what are we really estimating?As reference methods are not available for identifying low skeletal muscle mass in clinical practice, the European Group on Sarcopenia in Older People the Asian Working Group for Sarcopenia and the International Consensus for Cancer Cachexia guidelines accept bioelectrical impedance analysis (BIA) as an option for sarcopenia and cachexia assessment. Using different BIA equations, several components that represent ‘muscularity’ can be assessed. Total skeletal muscle mass or appendicular skeletal muscle mass normalized in relation to height (skeletal muscle mass index or appendicular skeletal muscle index, respectively) is the most common term used in the consensus. These terms are similar, but they should not be used as synonymous. Both terms can be used to define sarcopenia, but adequate equations and cut-off values should be used according to the studied population. However, there is a disagreement between the sarcopenia definition assessed by using BIA from the European Group on Sarcopenia in Older People and Cachexia Consensus, and this can lead to an overestimation of sarcopenia and, consequently, cachexia. An effort should be made to standardize the terminology employed by the Societies to define low muscularity and sarcopenia by using BIA. Future validation studies may show the need for specific cut-off values for each population using this method.

 

Gonzalez, M. C., and Heymsfield, S. B. (2017) Bioelectrical impedance analysis for diagnosing sarcopenia and cachexia: what are we really estimating?. Journal of Cachexia, Sarcopenia and Muscle, 8: 187189. doi: 10.1002/jcsm.12159.

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     Page 190201

Christopher Lipina, Harinder S Hundal

Lipid modulation of skeletal muscle mass and functionLoss of skeletal muscle mass is a characteristic feature of various pathologies including cancer, diabetes, and obesity, as well as being a general feature of ageing. However, the processes underlying its pathogenesis are not fully understood and may involve multiple factors. Importantly, there is growing evidence which supports a role for fatty acids and their derived lipid intermediates in the regulation of skeletal muscle mass and function. In this review, we discuss evidence pertaining to those pathways which are involved in the reduction, increase and/or preservation of skeletal muscle mass by such lipids under various pathological conditions, and highlight studies investigating how these processes may be influenced by dietary supplementation as well as genetic and/or pharmacological intervention.

 

Lipina, C., and Hundal, H. S. (2016) Lipid modulation of skeletal muscle mass and function. Journal of Cachexia, Sarcopenia and Muscle, 8: 190201. doi: 10.1002/jcsm.12144.

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     Page 202212

Hui Ding, Guohua Zhang, Ka Wai Thomas Sin, Zhelong Liu, Ren-Kuo Lin, Min Li, Yi-Ping Li

Activin A induces skeletal muscle catabolism via p38β mitogen-activated protein kinasesBackground
Activation of type IIB activin receptor (ActRIIB) in skeletal muscle leads to muscle atrophy because of increased muscle protein degradation. However, the intracellular signalling mechanism that mediates ActRIIB-activated muscle catabolism is poorly defined.
Methods
We investigated the role of p38β mitogen-activated protein kinases (MAPK) in mediating ActRIIB ligand activin A-activated muscle catabolic pathways in C2C12 myotubes and in mice with perturbation of this kinase pharmacologically and genetically.
Results
Treatment of C2C12 myotubes with activin A or myostatin rapidly activated p38 MAPK and its effector C/EBPβ within 1 h. Paradoxically, Akt was activated at the same time through a p38 MAPK-independent mechanism. These events were followed by up-regulation of ubiquitin ligases atrogin1 (MAFbx) and UBR2 (E3α-II), as well as increase in LC3-II, a marker of autophagosome formation, leading to myofibrillar protein loss and myotube atrophy. The catabolic effects of activin A were abolished by p38α/β MAPK inhibitor SB202190. Using small interfering RNA-mediated gene knockdown, we found that the catabolic activity of activin A was dependent on p38β MAPK specifically. Importantly, systemic administration of activin A to mice similarly activated the catabolic pathways in vivo, and this effect was blocked by SB202190. Further, activin A failed to activate the catabolic pathways in mice with muscle-specific knockout of p38β MAPK. Interestingly, activin A up-regulated MuRF1 in a p38 MAPK-independent manner, and MuRF1 did not appear responsible for activin A-induced myosin heavy chain loss and muscle atrophy.
Conclusions
ActRIIB-mediated activation of muscle catabolism is dependent on p38β MAPK-activated signalling.

 

Ding, H., Zhang, G., Sin, K. W. T., Liu, Z., Lin, R. -K., Li, M., and Li, Y. -P. (2016) Activin A induces skeletal muscle catabolism via p38β mitogen-activated protein kinases. Journal of Cachexia, Sarcopenia and Muscle, 8: 202212. doi: 10.1002/jcsm.12145.

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     Page 213228

Félix St-Jean-Pelletier, Charlotte H Pion, Jean-Philippe Leduc-Gaudet, Nicolas Sgarioto, Igor Zovilé, Sébastien Barbat-Artigas, Olivier Reynaud, Feras Alkaterji, François C Lemieux, Alexis Grenon, Pierrette Gaudreau, Russell T Hepple, Stéphanie Chevalier, Marc Belanger, José A Morais, Mylène Aubertin-Leheudre, Gilles Gouspillou

The impact of ageing, physical activity, and pre-frailty on skeletal muscle phenotype, mitochondrial content, and intramyocellular lipids in menBackground
The exact impact of ageing on skeletal muscle phenotype and mitochondrial and lipid content remains controversial, probably because physical activity, which greatly influences muscle physiology, is rarely accounted for. The present study was therefore designed to investigate the effects of ageing, physical activity, and pre-frailty on skeletal muscle phenotype, and mitochondrial and intramyocellular lipid content in men.
Methods
Recreationally active young adult (20–30 yo; YA); active (ACT) and sedentary (SED) middle-age (50–65 yo; MA-ACT and MA-SED); and older (65 + yo; 65 + ACT and 65 + SED) and pre-frail older (65 + PF) men were recruited. Muscle biopsies from the vastus lateralis were collected to assess, on muscle cross sections, muscle phenotype (using myosin heavy chain isoforms immunolabelling), the fibre type-specific content of mitochondria (by quantifying the succinate dehydrogenase stain intensity), and the fibre type-specific lipid content (by quantifying the Oil Red O stain intensity).
Results
Only 65 + SED and 65 + PF displayed significantly lower overall and type IIa fibre sizes vs. YA. 65 + SED displayed a lower type IIa fibre proportion vs. YA. MA-SED and 65 + SED displayed a higher hybrid type IIa/IIx fibre proportion vs. YA. Sedentary and pre-frail, but not active, men displayed lower mitochondrial content irrespective of fibre type vs. YA. 65 + SED, but not 65 + ACT, displayed a higher lipid content in type I fibres vs. YA. Finally, mitochondrial content, but not lipid content, was positively correlated with indices of muscle function, functional capacity, and insulin sensitivity across all subjects.
Conclusions
Taken altogether, our results indicate that ageing in sedentary men is associated with (i) complex changes in muscle phenotype preferentially affecting type IIa fibres; (ii) a decline in mitochondrial content affecting all fibre types; and (iii) an increase in lipid content in type I fibres. They also indicate that physical activity partially protects from the effects of ageing on muscle phenotype, mitochondrial content, and lipid accumulation. No skeletal specific muscle phenotype of pre-frailty was observed.

 

 

St-Jean-Pelletier, F., Pion, C. H., Leduc-Gaudet, J. -P., Sgarioto, N., Zovilé, I., Barbat-Artigas, S., Reynaud, O., Alkaterji, F., Lemieux, F. C., Grenon, A., Gaudreau, P., Hepple, R. T., Chevalier, S., Belanger, M., Morais, J. A., Aubertin-Leheudre, M., and Gouspillou, G. (2016) The impact of ageing, physical activity, and pre-frailty on skeletal muscle phenotype, mitochondrial content, and intramyocellular lipids in men. Journal of Cachexia, Sarcopenia and Muscle, 8: 213–228. doi: 10.1002/jcsm.12139.

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     Page 229–237

Richard Matthew Dodds, Antoneta Granic, Karen Davies, Thomas B. L. Kirkwood, Carol Jagger, Avan Aihie Sayer

Prevalence and incidence of sarcopenia in the very old: findings from the Newcastle 85+ StudyIntroduction
Recognition that an older person has sarcopenia is important because this condition is linked to a range of adverse outcomes. Sarcopenia becomes increasingly common with age, and yet there are few data concerning its descriptive epidemiology in the very old (aged 85 years and above). Our aims were to describe risk factors for sarcopenia and estimate its prevalence and incidence in a British sample of the very old.
Methods
We used data from two waves (2006/07 and 2009/10) of the Newcastle 85+ Study, a cohort born in 1921 and registered with a Newcastle/North Tyneside general practice. We assessed sarcopenia status using the European Working Group on Sarcopenia in Older People (EWGSOP) definition. Grip strength was measured using a Takei digital dynamometer (Takei Scientific Instruments Ltd., Niigata, Japan), gait speed was calculated from the Timed Up and Go test, and lean mass was estimated using a Tanita-305 body fat analyzer. We used logistic regression to examine associations between risk factors for prevalent sarcopenia at baseline and incident sarcopenia at follow-up.
Results
European Working Group on Sarcopenia in Older People sarcopenia was present in 21% of participants at baseline [149/719 participants, mean age 85.5 (0.4) years]. Many participants had either slow gait speed or weak grip strength (74.3%), and hence measurement of muscle mass was frequently indicated by the EWGSOP definition. Incidence data were available for 302 participants, and the incident rate was 3.7 cases per 100 person years at risk. Low Standardized Mini-Mental State Examination, lower occupational social class, and shorter duration of education were associated with sarcopenia at baseline, while low muscle mass was associated with incident sarcopenia. Low body mass index (BMI) was a risk factor for both in a graded fashion, with each unit decrease associated with increased odds of prevalent [odds ratio (OR) 1.29, 95% confidence interval (CI): 1.21, 1.37] and incident (OR 1.20, 95% CI: 1.08, 1.33) sarcopenia.
Conclusions
To our knowledge, this is the first study to describe prevalence and incidence of EWGSOP sarcopenia in the very old. Low BMI was a risk factor for both current and future sarcopenia; indeed, there was some evidence that low BMI may be a reasonable proxy for low lean mass. Overall, the high prevalence of sarcopenia among the very old suggests that this group should be a focus for future research.

 

Dodds, R. M., Granic, A., Davies, K., Kirkwood, T. B. L., Jagger, C., and Sayer, A. A. (2016) Prevalence and incidence of sarcopenia in the very old: findings from the Newcastle 85+ Study. Journal of Cachexia, Sarcopenia and Muscle, 8; 229–237. doi: 10.1002/jcsm.12157.

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     Page 238–244

Charlotte Beaudart, Emmanuel Biver, Jean-Yves Reginster, René Rizzoli, Yves Rolland, Ivan Bautmans, Jean Petermans, Sophie Gillain, Fanny Buckinx, Nadia Dardenne, Olivier Bruyère

Validation of the SarQoL®, a specific health-related quality of life questionnaire for SarcopeniaBackground
A specific self-administrated health-related quality of life questionnaire for sarcopenia, the Sarcopenia and Quality Of Life (SarQoL®), has been recently developed. This questionnaire is composed of 55 items translated into 22 questions and organized into seven domains of quality of life. The objective of the present work is to evaluate the psychometric properties (discriminative power, validity, reliability, floor and ceiling effects) of the SarQoL® questionnaire.
Methods
Sarcopenic subjects were recruited in an outpatient clinic in Liège, Belgium and were diagnosed according to the algorithm developed by the European Working Group on Sarcopenia in Older People. We compared the score of the SarQoL® between sarcopenic and non-sarcopenic subjects using a logistic regression after adjustment for potential confounding variables. Internal consistency reliability was determined using Cronbach's alpha coefficient; construct validity was assessed using convergent and divergent validities. Test–retest reliability was verified after a two-week interval using the intra-class correlation coefficient (ICC). At last, floor and ceiling effects were also tested.
Results
A total of 296 subjects with a median age of 73.3 (68.9–78.6) years were recruited for this study. Among them, 43 were diagnosed sarcopenic. After adjustment for potential confounding factors, the total score and the scores of the different dimensions of the SarQoL® questionnaire were significantly lower for sarcopenic than for non-sarcopenic subjects (54.7 (45.9–66.3) for sarcopenic vs. 67.8 (57.3 – 79.0) for non sarcopenic, OR 0.93 (95%CI 0.90–0.96)). Regarding internal consistency, the Cronbach's alpha coefficient was 0.87. The SarQoL® questionnaire data showed good correlation with some domains of the Short-Form 36 (SF-36) and the EuroQoL 5-dimension (EQ-5D) questionnaires and with the mobility test. An excellent agreement between the test and the retest was found with an ICC of 0.91 (95% CI 0.82–0.95). At last, neither floor nor ceiling effects were detected.
Conclusions
The SarQoL® questionnaire is valid, consistent, and reliable and can therefore be recommended for clinical and research purposes. However, its sensitivity to change needs to be assessed in future longitudinal studies.

 

Beaudart, C., Biver, E., Reginster, J. -Y., Rizzoli, R., Rolland, Y., Bautmans, I., Petermans, J., Gillain, S., Buckinx, F., Dardenne, N., and Bruyère, O. (2016) Validation of the SarQoL®, a specific health-related quality of life questionnaire for Sarcopenia. Journal of Cachexia, Sarcopenia and Muscle, 8: 238–244. doi: 10.1002/jcsm.12149.

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     Page 245–250

Leandro dos Santos, Edilson S. Cyrino, Melissa Antunes, Diana A. Santos, Luís B. Sardinha

Sarcopenia and physical independence in older adults: the independent and synergic role of muscle mass and muscle functionBackground
The loss of skeletal muscle mass (MM) or muscle function (MF) alone increases the risk for losing physical independence in older adults. We aimed to examine the independent and synergic associations of low MM and low MF, both criteria of sarcopenia, with the risk for losing projected physical independence in later life (+90?years old).
Methods
Cross-sectional analyses were conducted in 3493 non-institutionalized older adults (1166 males). Physical independence was assessed with a 12-item composite physical function scale. Logistic regression was used to estimate the odds-ratio (OR) for being at risk for losing physical independence.
Results
Approximately 30% of the participants were at risk for losing physical independence at 90?years of age. Independent analysis demonstrated that participants with low MM had 1.65 (95%CI: 1.27–2.31) increased odds for being at risk for losing physical independence and participants with low MF had 6.19 (95%CI 5.08–7.53) increased odds for being at risk. Jointly, having a low MM and a low MF increased the risk for losing physical independence to 12.28 (95%CI 7.95 to 18.96).
Conclusions
Although low MM represents a risk factor for losing physical independence, low MF seems to play a more dominant role in this relationship, with the presence of both sarcopenia criteria representing a substantial risk for losing physical independence in later life.

 

dos Santos, L., Cyrino, E. S., Antunes, M., Santos, D. A., and Sardinha, L. B. (2016) Sarcopenia and physical independence in older adults: the independent and synergic role of muscle mass and muscle function. Journal of Cachexia, Sarcopenia and Muscle, 8; 245–250. doi: 10.1002/jcsm.12160.

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     Page 251–258

Ming Yang, Xiaoyi Hu, Haozhong Wang, Lei Zhang, Qiukui Hao, Birong Dong

Sarcopenia predicts readmission and mortality in elderly patients in acute care wards: a prospective studyObjectives
The aim of this study is to assess the prevalence of sarcopenia and investigate the associations between sarcopenia and long-term mortality and readmission in a population of elderly inpatients in acute care wards.
Methods
We conducted a prospective observational study in the acute care wards of a teaching hospital in western China. The muscle mass was estimated according to a previously validated anthropometric equation. Handgrip strength was measured with a handheld dynamometer, and physical performance was measured via a 4 m walking test. Sarcopenia was defined according to the recommended diagnostic algorithm of the Asia Working Group for Sarcopenia. The survival status and readmission information were obtained via telephone interviews at 12, 24, and 36 months during the 3 year follow-up period following the baseline investigation.
Results
Two hundred and eighty-eight participants (mean age: 81.1 ± 6.6 years) were included. Forty-nine participants (17.0%) were identified as having sarcopenia. This condition was similar in men and women (16.9% vs. 17.5%, respectively, P = 0.915). During the 3 year follow-up period, 49 men (22.7%) and 9 women (16.4%) died (P = 0.307). The mortality of sarcopenic participants was significantly increased compared with non-sarcopenic participants (40.8% vs. 17.1%, respectively, P < 0.001). After adjusting for age, sex and other confounders, sarcopenia was an independent predictor of 3 year mortality (adjusted hazard ratio: 2.49; 95% confidential interval: 1.25–4.95) and readmission (adjusted hazard ratio: 1.81; 95% confidential interval: 1.17–2.80).
Conclusions
Sarcopenia, which is evaluated by a combination of anthropometric measures, gait speed, and handgrip strength, is valuable to predict hospital readmission and long-term mortality in elderly patients in acute care wards.


Yang, M., Hu, X., Wang, H., Zhang, L., Hao, Q., and Dong, B. (2016) Sarcopenia predicts readmission and mortality in elderly patients in acute care wards: a prospective study. Journal of Cachexia, Sarcopenia and Muscle, 8; 251–258. doi: 10.1002/jcsm.12163.

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     Page 259–266

Jinhee Kim, Yunhwan Lee, Seunghee Kye, Yoon-Sok Chung, Okhee Lee

Association of serum vitamin D with osteosarcopenic obesity: Korea National Health and Nutrition Examination Survey 2008–2010Background
Serum vitamin D levels have been reported to be associated with individual components of body composition. However, the relationship between serum vitamin D and combined indices of adverse body composition is largely unknown. This cross-sectional study examined the association between serum vitamin D and osteosarcopenic obesity in a nationally representative sample of middle-aged and older adults.
Methods
We analysed the Korea National Health and Nutrition Examination Surveys (IV and V) conducted in 2008–2010, consisting of 5908 (2485 men, 3423 women) aged =?50?years. Serum vitamin D levels were determined by radioimmunoassay, and body composition was evaluated by dual-energy x-ray absorptiometry. The association between serum vitamin D levels and the number of abnormalities in body composition, including osteosarcopenic obesity, a low bone and muscle mass with concurrent high fat mass, was analysed by multinomial logistic regression adjusting for covariates.
Results
In men, after controlling for covariates, higher vitamin D levels were associated with a significantly reduced likelihood of the number of phenotypes of adverse body composition (P for trend?<?0.05). Those in the highest tertile group of serum vitamin D levels, compared with those in the lowest tertile, were less likely to have adverse body composition, numbering one (odds ratio [OR]?=?0.67, 95% confidence interval [CI]: 0.49, 0.92), two (OR?=?0.49, 95% CI: 0.33, 0.73), and three (osteosarcopenic obesity; OR?=?0.42, 95% CI: 0.26, 0.67). In women, those in the highest tertile group of serum vitamin D levels, compared with those in the lowest tertile, were less likely to have osteosarcopenic obesity (OR?=?0.55, 95% CI: 0.33, 0.93). Vitamin D deficiency (<20?ng/mL) in men was significantly associated with an increased likelihood of a higher number of adverse body composition, especially for osteosarcopenic obesity (OR?=?2.08, 95% CI: 1.42, 3.03). Vitamin D deficient women, compared with those having normal levels of serum vitamin D, were also more likely to demonstrate osteosarcopenic obesity (OR?=?1.99, 95% CI: 1.30, 3.05).
Conclusions
A high serum vitamin D level in mid- and late-life was associated with reduced odds of multiple adverse body composition, especially osteosarcopenic obesity, suggesting potential health benefits of maintaining adequate levels of vitamin D.

 

Kim, J., Lee, Y., Kye, S., Chung, Y. -S., and Lee, O. (2016) Association of serum vitamin D with osteosarcopenic obesity: Korea National Health and Nutrition Examination Survey 2008–2010. Journal of Cachexia, Sarcopenia and Muscle, 8; 259–266. doi: 10.1002/jcsm.12154.

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     Page 267–276

Tim Snijders, Joshua P. Nederveen, Sophie Joanisse, Marika Leenders, Lex B. Verdijk, Luc J.C. van Loon, Gianni Parise

Muscle fibre capillarization is a critical factor in muscle fibre hypertrophy during resistance exercise training in older menBackground
Adequate muscle fibre perfusion is critical for the maintenance of muscle mass; it is essential in the rapid delivery of oxygen, nutrients and growth factors to the muscle, stimulating muscle fibre growth. Muscle fibre capillarization is known to decrease substantially with advancing age. However, whether (relative) low muscle fibre capillarization negatively impacts the muscle hypertrophic response following resistance exercise training in older adults is unknown.
Methods
Twenty-two healthy older men (71 ± 1 years) performed 24 weeks of progressive resistance type exercise training. To assess the change in muscle fibre characteristics, percutaneous biopsies from the vastus lateralis muscle were taken before and following 12 and 24 weeks of the intervention programme. A comparison was made between participants who had a relatively low type II muscle fibre capillary-to-fibre perimeter exchange index (CFPE; LOW group) and high type II muscle fibre CFPE (HIGH group) at baseline. Type I and type II muscle fibre size, satellite cell, capillary content and distance between satellite cells to the nearest capillary were determined by immunohistochemistry.
Results
Overall, type II muscle fibre size (from 5150 ± 234 to 6719 ± 446 µm2, P < 0.05) and satellite cell content (from 0.058 ± 0.006 to 0.090 ± 0.010 satellite cells per muscle fibre, P  < 0.05) had increased significantly in response to 24 weeks of resistance exercise training. However, these improvements where mainly driven by differences in baseline type II muscle fibre capillarization, whereas muscle fibre size (from 5170 ± 390 to 7133 ± 314 µm2, P < 0.05) and satellite cell content (from 0.059 ± 0.009 to 0.102 ± 0.017 satellite cells per muscle fibre, P  < 0.05) increased significantly in the HIGH group, no significant changes were observed in LOW group following exercise training. No significant changes in type I and type II muscle fibre capillarization were observed in response to 12 and 24 weeks of resistance exercise training in both the LOW and HIGH group.
Conclusions
Type II muscle fibre capillarization at baseline may be a critical factor for allowing muscle fibre hypertrophy to occur during prolonged resistance exercise training in older men.

 

Snijders, T., Nederveen, J. P., Joanisse, S., Leenders, M., Verdijk, L. B., van Loon, L. J. C., and Parise, G. (2016) Muscle fibre capillarization is a critical factor in muscle fibre hypertrophy during resistance exercise training in older men. Journal of Cachexia, Sarcopenia and Muscle, 8; 267–276. doi: 10.1002/jcsm.12137.

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     Page 277–284

Sheng-Chih Huang, Jin-Fu Wu, Suchada Saovieng, Wei-Horng Chien, Ming-Fen Hsu, Xiao-Fei Li, Shin-Da Lee, Chih-Yang Huang, Chih-Yang Huang, Chia-Hua Kuo

Doxorubicin inhibits muscle inflammation after eccentric exerciseBackground
Doxorubicin, a widely used anti-tumour drug, is known to cause muscle loss in cancer patients.
Methods
Following an acute dose of doxorubicin injection (2.5 mg/kg per body weight), we examined macrophage distribution in rat soleus muscle challenged by eccentric exercise (downhill running). Long-term doxorubicin treatment (one injection every 3 days) on muscle mass and survival were also determined.
Results
Under non-exercised condition, increased tumour necrosis factor (TNF)-alpha mRNA and decreased IL-10 mRNA were observed in soleus muscle of doxorubicin-treated rats, compared with saline-treated control rats. However, increases in inflammation score (leukocyte infiltration), nitrotyrosine level, and M1 macrophage (CD68+) invasion in exercised soleus muscle were absent in doxorubicin-treated rats, whereas increased M2 macrophage (CD163+) localization in exercised muscle was less affected by doxorubicin. Despites coenzyme Q (Q10) supplementation significantly elevated TNF-alpha mRNA, nitrotyrosine, and anti-oxidant gamma-glutamylcysteine synthetase (GCS) levels in non-exercised soleus muscle, these pro-inflammatory responses were also abolished in doxorubicin-treated rats. Results from long-term doxorubicin treatment show a significant muscle loss followed by an accelerated death, which cannot be reversed by Q10 supplementation.
Conclusions
(i) Doxorubicin impairs inflammation mechanism by depleting M1 macrophage in exercised skeletal muscle; (ii) Muscle loss and accelerated death during prolonged doxorubicin treatment cannot be reversed by Q10 supplementation.

 

Huang, S. -C., Wu, J. -F., Saovieng, S., Chien, W. -H., Hsu, M. -F., Li, X. -F., Lee, S. -D., Huang, C. -Y., Huang, C. -Y., and Kuo, C. -H. (2016) Doxorubicin inhibits muscle inflammation after eccentric exercise. Journal of Cachexia, Sarcopenia and Muscle, 8; 277–284. doi: 10.1002/jcsm.12148.

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     Page 285297

Jeroen L.A. van Vugt, Stef Levolger, Arvind Gharbharan, Marcel Koek, Wiro J. Niessen, Jacobus W.A. Burger, Sten P. Willemsen, Ron W.F. de Bruin, Jan N.M. IJzermans

A comparative study of software programmes for cross-sectional skeletal muscle and adipose tissue measurements on abdominal computed tomography scans of rectal cancer patientsBackground
The association between body composition (e.g. sarcopenia or visceral obesity) and treatment outcomes, such as survival, using single-slice computed tomography (CT)-based measurements has recently been studied in various patient groups. These studies have been conducted with different software programmes, each with their specific characteristics, of which the inter-observer, intra-observer, and inter-software correlation are unknown. Therefore, a comparative study was performed.
Methods
Fifty abdominal CT scans were randomly selected from 50 different patients and independently assessed by two observers. Cross-sectional muscle area (CSMA, i.e. rectus abdominis, oblique and transverse abdominal muscles, paraspinal muscles, and the psoas muscle), visceral adipose tissue area (VAT), and subcutaneous adipose tissue area (SAT) were segmented by using standard Hounsfield unit ranges and computed for regions of interest. The inter-software, intra-observer, and inter-observer agreement for CSMA, VAT, and SAT measurements using FatSeg, OsiriX, ImageJ, and sliceOmatic were calculated using intra-class correlation coefficients (ICCs) and Bland–Altman analyses. Cohen's κ was calculated for the agreement of sarcopenia and visceral obesity assessment. The Jaccard similarity coefficient was used to compare the similarity and diversity of measurements.
Results
Bland–Altman analyses and ICC indicated that the CSMA, VAT, and SAT measurements between the different software programmes were highly comparable (ICC 0.979–1.000, P < 0.001). All programmes adequately distinguished between the presence or absence of sarcopenia (κ = 0.88–0.96 for one observer and all κ = 1.00 for all comparisons of the other observer) and visceral obesity (all κ = 1.00). Furthermore, excellent intra-observer (ICC 0.999–1.000, P < 0.001) and inter-observer (ICC 0.998–0.999, P < 0.001) agreement for all software programmes were found. Accordingly, excellent Jaccard similarity coefficients were found for all comparisons (mean ≥ 0.964).
Conclusions
FatSeg, OsiriX, ImageJ, and sliceOmatic showed an excellent agreement for CSMA, VAT, and SAT measurements on abdominal CT scans. Furthermore, excellent inter-observer and intra-observer agreement were achieved. Therefore, results of studies using these different software programmes can reliably be compared.

 


van Vugt, J. L. A., Levolger, S., Gharbharan, A., Koek, M., Niessen, W. J., Burger, J. W. A., Willemsen, S. P., de Bruin, R. W. F., and IJzermans, J. N. M. (2016) A comparative study of software programmes for cross-sectional skeletal muscle and adipose tissue measurements on abdominal computed tomography scans of rectal cancer patients. Journal of Cachexia, Sarcopenia and Muscle, 8; 285297. doi: 10.1002/jcsm.12158.

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     Page 298–304

Michael P. Chu, Jessica Lieffers, Sunita Ghosh, Andrew Belch, Neil S. Chua, Amelie Fontaine, Randeep Sangha, Robert A. Turner, Vickie E. Baracos andMichael B. Sawyer

Skeletal muscle density is an independent predictor of diffuse large B-cell lymphoma outcomes treated with rituximab-based chemoimmunotherapyBackground
While much cancer research focuses on tumours and their microenvironment, malignancies cause widespread physiologic changes. Cancer and treatment-related sarcopenia, measured with quantitative imaging or as a decrease in overall body mass, are indicative of poor prognosis in elderly diffuse large B-cell lymphoma (DLBCL) patients, skeletal muscle radiodensity (SMD) may be a better prognostic marker. SMD, a measure of muscle radiation attenuation on CT imaging, is more prognostic than sarcopenia or International Prognostic Index (IPI) scores in follicular lymphoma and multiple solid organ malignancies. Low SMD appears to correlate with fat accumulation in muscle and is associated with inflammation. This study set out to examine SMD's prognostic ability in DLBCL.
Methods
All DLBCL patients treated with rituximab-containing therapy between 2004 and 2009 were compared to determine SMD's prognostic ability in this single centre, retrospective study. Pre-treatment CT scans were used to measure SMD and muscle cross-sectional area. Primary endpoints included progression free (PFS) and overall survival (OS) while objective response rates (ORR) were secondary.
Results
Of 224 evaluable patients, 116 were identified as having low SMD. Low SMD predicted poorer 5 year PFS, 60 vs. 81% (p = 0.001) and OS, 58 vs. 86% (p < 0.0001). SMD's prognostic ability retained significance in multivariate analysis taking into consideration the Revised International Prognostic Index (R-IPI) and sex. Although high SMD was not predictive of ORR (95.4 vs. 91.4%, p = 0.17), it was strongly associated with radiographic complete response (85 vs. 66%, p = 0.0007). Contrary to previous findings, sarcopenia did not predict for poorer OS but suggested improved OS in elderly DLBCL patients (HR 0.38, p = 0.01).
Conclusions
SMD is a novel prognostic (and potentially treatment predictive) marker independent of R-IPI in DLBCL. It presents an inexpensive yet complementary assessment to R-IPI for prognosticating DLBCL outcomes.

 


Chu, M. P., Lieffers, J., Ghosh, S., Belch, A., Chua, N. S., Fontaine, A., Sangha, R., Turner, R. A., Baracos, V. E., and Sawyer, M. B. (2016) Skeletal muscle density is an independent predictor of diffuse large B-cell lymphoma outcomes treated with rituximab-based chemoimmunotherapy. Journal of Cachexia, Sarcopenia and Muscle, 8; 298–304. doi: 10.1002/jcsm.12161.

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     Page 305–316

Oliver Klassen, Martina E. Schmidt, Cornelia M. Ulrich, Andreas Schneeweiss, Karin Potthoff, Karen Steindorf, Joachim Wiskemann

Muscle strength in breast cancer patients receiving different treatment regimesBackground
Muscle dysfunction and sarcopenia have been associated with poor performance status, an increased mortality risk, and greater side effects in oncologic patients. However, little is known about how performance is affected by cancer therapy. We investigated muscle strength in breast cancer patients in different adjuvant treatment settings and also compared it with data from healthy individuals.
Methods
Breast cancer patients (N = 255) from two randomized controlled exercise trials, staged 0–III and aged 54.4 ± 9.4 years, were categorized into four groups according to their treatment status. In a cross-sectional design, muscle function was assessed bilaterally by isokinetic dynamometry (0°, 60°, 180°/s) as maximal voluntary isometric contraction (MVIC) and maximal isokinetic peak torque (MIPT) in shoulder rotators and knee flexors and extensors. Additionally, muscular fatigue index (FI%) and shoulder flexibility were evaluated. Healthy women (N = 26), aged 53.3 ± 9.8 years, were tested using the same method. Analysis of covariance was used to estimate the impact of different cancer treatments on skeletal muscle function with adjustment for various clinical and socio-demographic factors.
Results
Consistently, lower muscle strength was measured in shoulder and knee strength in patients after chemotherapy. On average, patients had up to 25% lower strength in lower extremities and 12–16% in upper extremities in MVIC and MIPT during cancer treatment compared with healthy women. No substantial difference between patient groups in shoulder strength, but significantly lower shoulder flexibility in patients with radical mastectomy was measured. Chemotherapy-treated patients had consistently higher FI%. No serious adverse events were reported.
Conclusions
Breast cancer patients showed markedly impaired muscle strength and joint dysfunctions before and after anticancer treatment. The significant differences between patients and healthy individuals underline the need of exercise therapy as early as possible in order to prevent or counteract the loss of muscle function after curative surgery as well as the consequences of neo-/adjuvant chemotherapy.

 

Klassen, O., Schmidt, M. E., Ulrich, C. M., Schneeweiss, A., Potthoff, K., Steindorf, K., and Wiskemann, J. (2016) Muscle strength in breast cancer patients receiving different treatment regimes. Journal of Cachexia, Sarcopenia and Muscle, 8; 305–316. doi: 10.1002/jcsm.12165.

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     Page 317–326

David P. J. van Dijk, Maikel J. A. M. Bakens, Mariëlle M. E. Coolsen, Sander S. Rensen, Ronald M. van Dam, Martijn J. L. Bours, Matty P. Weijenberg, Cornelis H. C. Dejong, Steven W. M. Olde Damink

Low skeletal muscle radiation attenuation and visceral adiposity are associated with overall survival and surgical site infections in patients with pancreatic cancerBackground
Cancer cachexia and skeletal muscle wasting are related to poor survival. In this study, quantitative body composition measurements using computed tomography (CT) were investigated in relation to survival, post-operative complications, and surgical site infections in surgical patients with cancer of the head of the pancreas.
Methods
A prospective cohort of 199 patients with cancer of the head of the pancreas was analysed by CT imaging at the L3 level to determine (i) muscle radiation attenuation (average Hounsfield units of total L3 skeletal muscle); (ii) visceral adipose tissue area; (iii) subcutaneous adipose tissue area; (iv) intermuscular adipose tissue area; and (v) skeletal muscle area. Sex-specific cut-offs were determined at the lower tertile for muscle radiation attenuation and skeletal muscle area and the higher tertile for adipose tissues. These variables of body composition were related to overall survival, severe post-operative complications (Dindo–Clavien ≥ 3), and surgical site infections (wounds inspected daily by an independent trial nurse) using Cox-regression analysis and multivariable logistic regression analysis, respectively.
Results
Low muscle radiation attenuation was associated with shorter survival in comparison with moderate and high muscle radiation attenuation [median survival 10.8 (95% CI: 8.8–12.8) vs. 17.4 (95% CI: 14.7–20.1), and 18.5 (95% CI: 9.2–27.8) months, respectively; P < 0.008]. Patient subgroups with high muscle radiation attenuation combined with either low visceral adipose tissue or age <70 years had longer survival than other subgroups (P = 0.011 and P = 0.001, respectively). Muscle radiation attenuation was inversely correlated with intermuscular adipose tissue (rp = −0.697, P < 0.001). High visceral adipose tissue was associated with an increased surgical site infection rate, OR: 2.4 (95% CI: 1.1–5.3; P = 0.027).
Conclusions
Low muscle radiation attenuation was associated with reduced survival, and high visceral adiposity was associated with an increase in surgical site infections. The strong correlation between muscle radiation attenuation and intermuscular adipose tissue suggests the presence of ectopic fat in muscle, warranting further investigation. CT image analysis could be implemented in pre-operative risk assessment to assist in treatment decision-making.

 

 

van Dijk, D. P. J., Bakens, M. J. A. M., Coolsen, M. M. E., Rensen, S. S., van Dam, R. M., Bours, M. J. L., Weijenberg, M. P., Dejong, C. H. C., and Olde Damink, S. W. M. (2016) Low skeletal muscle radiation attenuation and visceral adiposity are associated with overall survival and surgical site infections in patients with pancreatic cancer. Journal of Cachexia, Sarcopenia and Muscle, 8; 317–326. doi: 10.1002/jcsm.12155.

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     Page 302–312

Rizhen Yu, Ji-an Chen, Jing Xu, Jin Cao, Yanlin Wang, Sandhya S. Thomas, Zhaoyong Hu

Suppression of muscle wasting by the plant-derived compound ursolic acid in a model of chronic kidney diseaseBackground
Muscle wasting in chronic kidney disease (CKD) and other catabolic disorders contributes to morbidity and mortality, and there are no therapeutic interventions that regularly and safely block losses of muscle mass. We have obtained evidence that impaired IGF-1/insulin signalling and increases in glucocorticoids, myostatin and/or inflammatory cytokines that contribute to the development of muscle wasting in catabolic disorders by activating protein degradation.
Methods
Using in vitro and in vivo models of muscle wasting associated with CKD or dexamethasone administration, we measured protein synthesis and degradation and examined mechanisms by which ursolic acid, derived from plants, could block the loss of muscle mass stimulated by CKD or excessive levels of dexamethasone.
Results
Using cultured C2C12 myotubes to study muscle wasting, we found that exposure to glucocorticoids cause loss of cell proteins plus an increase in myostatin; both responses are significantly suppressed by ursolic acid. Results from promoter and ChIP assays demonstrated a mechanism involving ursolic acid blockade of myostatin promoter activity that is related to CEBP/δ expression. In mouse models of CKD-induced or dexamethasone-induced muscle wasting, we found that ursolic acid blocked the loss of muscle mass by stimulating protein synthesis and decreasing protein degradation. These beneficial responses included decreased expression of myostatin and inflammatory cytokines (e.g. TGF-β, IL-6 and TNFα), which are initiators of muscle-specific ubiquitin-E3 ligases (e.g. Atrogin-1, MuRF-1 and MUSA1).
Conclusions
Ursolic acid improves CKD-induced muscle mass by suppressing the expression of myostatin and inflammatory cytokines via increasing protein synthesis and reducing proteolysis.

 

Yu, R., Chen, J., Xu, J., Cao, J., Wang, Y., Thomas, S. S., and Hu, Z. (2016) Suppression of muscle wasting by the plant-derived compound ursolic acid in a model of chronic kidney disease. Journal of Cachexia, Sarcopenia and Muscle, 8; 302–312. doi: 10.1002/jcsm.12162.

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Number 3 / June 2017

 

     Page 239245

Jens Fielitz

Cancer cachexia - when proteasomal inhibition is not enoughno abstract

 

Fielitz, J. (2016) Cancer cachexia—when proteasomal inhibition is not enough. Journal of Cachexia, Sarcopenia and Muscle, 7: 239–245. doi: 10.1002/jcsm.12124.

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     Page 246–260

Goran Loncar, Jochen Springer, Markus Anker, Wolfram Doehner, Mitja Lainscak

Cardiac cachexia: hic et nuncCardiac cachexia (CC) is the clinical entity at the end of the chronic natural course of heart failure (HF). Despite the efforts, even the most recent definition of cardiac cachexia has been challenged, more precisely, the addition of new criteria on top of obligatory weight loss. The pathophysiology of CC is complex and multifactorial. A better understanding of pathophysiological pathways in body wasting will contribute to establish potentially novel treatment strategies. The complex biochemical network related with CC and HF pathophysiology underlines that a single biomarker cannot reflect all of the features of the disease. Biomarkers that could pick up the changes in body composition before they convey into clinical manifestations of CC would be of great importance. The development of preventive and therapeutic strategies against cachexia, sarcopenia, and wasting disorders is perceived as an urgent need by healthcare professionals. The treatment of body wasting remains an unresolved challenge to this day. As CC is a multifactorial disorder, it is unlikely that any single agent will be completely effective in treating this condition. Among all investigated therapeutic strategies, aerobic exercise training in HF patients is the most proved to counteract skeletal muscle wasting and is recommended by treatment guidelines for HF.

 

Loncar, G., Springer, J., Anker, M., Doehner, W., and Lainscak, M. (2016) Cardiac cachexia: hic et nunc. Journal of Cachexia, Sarcopenia and Muscle, 7: 246–260. doi: 10.1002/jcsm.12118.

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     Page 269271

Tahnee Sente, An M Van Berendoncks, Vicky Y Hoymans, Christiaan J Vrints

Adiponectin resistance in skeletal muscle: pathophysiological implications in chronic heart failureSkeletal muscle wasting is a common complication of chronic heart failure (CHF) and linked to poor patient prognosis. In recent years, adiponectin was postulated to be centrally involved in CHF-associated metabolic failure and muscle wasting. This review discusses current knowledge on the role of adiponectin in CHF. Particular emphasis will be given to the complex interaction mechanisms and the intracellular pathways underlying adiponectin resistance in skeletal muscle of CHF patients. In this review, we propose that the resistance process is multifactorial, integrating abnormalities emanating from insulin signalling, mitochondrial biogenesis, and ceramide metabolism.

 

Sente, T., Van Berendoncks, A. M., Hoymans, V. Y., and Vrints, C. J. (2016) Adiponectin resistance in skeletal muscle: pathophysiological implications in chronic heart failure. Journal of Cachexia, Sarcopenia and Muscle, 7: 261274. doi: 10.1002/jcsm.12086.

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     Page 275283

Yi Chao Foong, Nabil Chherawala, Dawn Aitken, David Scott, Tania Winzenberg, Graeme Jones

Accelerometer-determined physical activity, muscle mass, and leg strength in community-dwelling older adultsIntroduction
The aim of this study was to describe the relationship between accelerometer-determined physical activity (PA), muscle mass, and lower-limb strength in community-dwelling older adults.
Methods
Six hundred thirty-six community-dwelling older adults (66 ± 7 years) were studied. Muscle mass was measured using dual-energy x-ray absorptiometry, whilst lower limb strength was measured via dynamometry. We measured minutes/day spent in sedentary, light, moderate, and vigorous intensity activity using Actigraph GT1M accelerometers.
Results
Participants spent a median of 583(Interquartile ratio (IQR) 522–646), 225(176–271), 27(12–45) and 0(0–0) min in sedentary, light, moderate, and vigorous activity, respectively. PA intensity was positively associated with both lean mass percentage and lower limb strength in a dose–response fashion. Sedentary activity was negatively associated with lean mass percentage, but not lower-limb strength. There was a positive association between PA and appendicular lean mass in men only. There was an interaction between age and activity; as age increased, the magnitude of the association of PA with lean mass percentage decreased. Those who adhered to the Australian Department of Health PA guidelines (moderate/vigorous PA >/=150 min/week) had greater lean mass percentage, appendicular lean mass, and lower limb strength.
Conclusions
Using accelerometer technology, both the amount and intensity of accelerometer-determined PA had an independent, dose–response relationship with lean mass percentage and lower limb strength, with the largest effect for vigorous activity. Time spent in sedentary activity was negatively associated with lean mass percentage, but was not associated with lower limb strength. The magnitude of the association between PA and lean mass percentage decreased with age, suggesting that PA programmes may need to be modified with increasing age.

 

Foong, Y. C., Chherawala, N., Aitken, D., Scott, D., Winzenberg, T., and Jones, G. (2016) Accelerometer-determined physical activity, muscle mass, and leg strength in community-dwelling older adults. Journal of Cachexia, Sarcopenia and Muscle, 7: 275283. doi: 10.1002/jcsm.12065.

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     Page 284289

Sébastien Barbat-Artigas, Sophie Garnier, Sandra Joffroy, Éléonor Riesco, Frédéric Sanguignol, Bruno Vellas, Yves Rolland, Sandrine Andrieu, Mylène Aubertin-Leheudre, Pascale Mauriège

Caloric restriction and aerobic exercise in sarcopenic and non-sarcopenic obese women: an observational and retrospective studyBackground
Sarcopenic obese (SO) individuals are a unique subset of subjects that combines obesity and sarcopenia. Traditional weight loss programmes including aerobic exercises may worsen their condition by further reducing their lean mass. The objective of this observational and retrospective study was to verify the effect of a mixed weight loss programme combining caloric restriction and exercise on body composition, and lipid-lipoprotein profile of obese women according to their sarcopenic status.
Methods
One hundred and forty-six obese women (body mass index ≥ 30 kg/m2 and fat mass ≥ 40%) participated to the 3 week usual and institutionalized weight-reducing programme combining a dietary plan (1400 ± 200 kcal/day) and aerobic exercise (1 h/day, 6 days/week) of a specialized medical institution. The lean body mass index (LMI; lean mass/height2) was calculated, and women in the lowest tertile of LMI were considered SO.
Results
At baseline, SO women were older, and their body weight and LMI were lower than non-sarcopenic obese (N-SO) women (p < 0.05). N-SO and SO women similarly lost fat mass and improved their lipid-lipoprotein profile (p  < 0.05), while differences in LMI between groups persisted at the end of the weight-reducing programme. Indeed, N-SO women lost lean mass (p < 0.05) while SO did not.
Conclusions
These findings suggest that a short weight loss programme combining caloric restriction and aerobic exercise may significantly reduce fat mass and improve lipid-lipoprotein profile in obese women, independently of their sarcopenic status. Such programmes may have deleterious effects on lean mass in N-SO subjects, only.

 

Barbat-Artigas, S., Garnier, S., Joffroy, S., Riesco, É., Sanguignol, F., Vellas, B., Rolland, Y., Andrieu, S., Aubertin-Leheudre, M., and Mauriège, P. (2016) Caloric restriction and aerobic exercise in sarcopenic and non-sarcopenic obese women: an observational and retrospective study. Journal of Cachexia, Sarcopenia and Muscle, 7: 284289. doi: 10.1002/jcsm.12075.

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     Page 290298

Justin C. Brown, Michael O. Harhay, Meera N. Harhay

Sarcopenia and mortality among a population-based sample of community-dwelling older adultsBackground
Sarcopenia is a risk-factor for all-cause mortality among older adults, but it is unknown if sarcopenia predisposes older adults to specific causes of death. Further, it is unknown if the prognostic role of sarcopenia differs between males and females, and obese and non-obese individuals.
Methods
A population-based cohort study among 4425 older adults from the Third National Health and Nutrition Survey (1988–1994). Muscle mass was quantified using bioimpedance analysis, and muscle function was quantified using gait speed. Multivariable-adjusted Cox regression analysis examined the relationship between sarcopenia and mortality outcomes.
Results
The mean age of study participants was 70.1 years. The prevalence of sarcopenia was 36.5%. Sarcopenia associated with an increased risk of all-cause mortality [hazard ratio (HR): 1.29 (95% confidence interval (95% CI): 1.13–1.47); P < 0.001] among males and females. Sarcopenia associated with an increased risk of cardiovascular-specific mortality among females [HR: 1.61 (95% CI: 1.22–2.12); P = 0.001], but not among males [HR: 1.07 (95% CI: 0.81–1.40; P = .643); Pinteraction = 0.079]. Sarcopenia was not associated with cancer-specific mortality among males and females [HR: 1.07 (95% CI: 0.78–1.89); P  = 0.672]. Sarcopenia associated with an increased risk of mortality from other causes (i.e. non-cardiovascular and non-cancer) among males and females [HR: 1.32 (95% CI: 1.07–1.62); P = 0.008]. Obesity, defined using body mass index (Pinteraction = 0.817) or waist circumference (Pinteraction = 0.219) did not modify the relationship between sarcopenia and all-cause mortality.
Conclusions
Sarcopenia is a prevalent syndrome that is associated with premature mortality among community-dwelling older adults. The prognostic value of sarcopenia may vary by cause-specific mortality and differ between males and females.

 

Brown, J. C., Harhay, M. O., and Harhay, M. N. (2016) Sarcopenia and mortality among a population-based sample of community-dwelling older adults. Journal of Cachexia, Sarcopenia and Muscle, 7: 290298. doi: 10.1002/jcsm.12073.

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     Page 299311

Pawel Szulc, Clément Feyt, Roland Chapurlat

High risk of fall, poor physical function, and low grip strength in men with fracture—the STRAMBO studyBackground
Several studies assessed the association of prevalent fractures with muscle mass, strength, and physical capacity in men. Clinical impact of these associations is not clear, and they could be influenced by confounders. Our aim was to assess the association of the prevalent fractures with muscle strength, physical function, and the risk of subsequent falls in older men after adjustment for muscle mass and potential confounders.
Methods
In a cohort of 890 men aged 50 and older, we assessed appendicular skeletal muscle mass (ASM) by DXA, grip strength, physical function (chair stands, static, and dynamic balance). Relative ASM (RASM) was calculated as ASM / (height)2. Then, 813 men aged 60 and over were followed up prospectively for 5 years and 144 sustained >1 incident falls. All the analyses were adjusted for lifestyle factors, co-morbidities, and hormones known to influence muscle and physical function.
Results
Low leisure physical activity, very high occupational physical activity, Parkinson's disease, diabetes mellitus, low apparent free testosterone concentration (AFTC), as well as Grade 2 and 3 vertebral fractures and multiple fractures were associated with lower grip strength when adjusted for confounders including upper limb RASM. Low leisure physical activity, very high occupational physical activity, diabetes mellitus, prior stroke, low AFTC and 25-hydroxycholecalciferol, high C-reactive protein, vertebral fractures, and non-vertebral fractures were associated with poor physical function (lowest quintile of the score of tests) when adjusted for confounders including lower limb RASM. Grade 2 and 3 and multiple vertebral fractures were associated with twofold higher risk of multiple falls after adjustment for confounders. Men having multiple fractures had a twofold higher risk of multiple falls after adjusting for confounders. In multivariable models, risk of falls increased proportionally to the increasing severity and number of vertebral fractures as well as to the increasing number of all fractures.
Conclusions
In older men, Grade 2 and 3 vertebral fractures and multiple vertebral and non-vertebral fractures are associated with lower grip strength, poor physical function, and higher risk of multiple falls after adjustment for multiple confounders. This suggests a real direct association. One fracture can initiate a vicious circle leading to another fracture; thus, patients with fractures need physical therapy regardless of their general health status.

 

Szulc, P., Feyt, C., and Chapurlat, R. (2016) High risk of fall, poor physical function, and low grip strength in men with fracture—the STRAMBO study. Journal of Cachexia, Sarcopenia and Muscle, 7: 299311. doi: 10.1002/jcsm.12066.

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     Page 312321

Stefanos Tyrovolas, Ai Koyanagi, Beatriz Olaya1, Jose Luis Ayuso-Mateos, Marta Miret, Somnath Chatterji, Beata Tobiasz-Adamczyk, Seppo Koskinen, Matilde Leonardi,
Josep Maria Haro

Factors associated with skeletal muscle mass, sarcopenia, and sarcopenic obesity in older adults: a multi-continent studyBackground
The aim of this study was to evaluate the factors associated with low skeletal muscle mass (SMM), sarcopenia, and sarcopenic obesity using nationally representative samples of people aged ≥65 years from diverse geographical regions of the world.
Methods
Data were available for 18 363 people aged ≥65 years who participated in the Collaborative Research on Ageing in Europe survey conducted in Finland, Poland, and Spain, and the World Health Organization Study on global AGEing and adult health survey conducted in China, Ghana, India, Mexico, Russia, and South Africa, between 2007 and 2012. A skeletal muscle mass index (SMI) was created to reflect SMM. SMM, SMI, and percent body fat (%BF) were calculated with specific indirect population formulas. These estimates were based on age, sex, weight, height, and race. Sarcopenia and sarcopenic obesity were defined with specific cut-offs.
Results
The prevalence of sarcopenia ranged from 12.6% (Poland) to 17.5% (India), and that of sarcopenic obesity ranged from 1.3% (India) to 11.0% (Spain). Higher %BF was associated with lower SMM in all countries, and with sarcopenia in five countries (p < 0.001). Compared to high levels of physical activity, low levels were related with higher odds for sarcopenia [OR 1.36 (95%CI 1.11–1.67)] and sarcopenic obesity [OR 1.80 (95%CI 1.23–2.64)] in the overall sample. Also, a dose-dependent association between higher numbers of chronic diseases and sarcopenic obesity was observed.
Conclusions
Physical activity and body composition changes such as high %BF are key factors for the prevention of sarcopenia syndrome.

 

Tyrovolas, S., Koyanagi, A., Olaya, B., Ayuso-Mateos, J. L., Miret, M., Chatterji, S., Tobiasz-Adamczyk, B., Koskinen, S., Leonardi, M., and Haro, J. M. (2016) Factors associated with skeletal muscle mass, sarcopenia, and sarcopenic obesity in older adults: a multi-continent study. Journal of Cachexia, Sarcopenia and Muscle, 7: 312321. doi: 10.1002/jcsm.12076.

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     Page 322329

Sang Yoon Lee, Won Kim, Hee-Won Park, Sang Chul Park, In Kwon Kim, Sun G. Chung

Anti-sarcopenic effects of diamino-diphenyl sulfone observed in elderly female leprosy survivors: a cross-sectional studyBackground
It has been reported that 4,4′-diamino-diphenyl sulfone (DDS), the longtime treatment of choice for leprosy, prolongs the lifespan and increases mobility in animal models by reducing the levels of reactive oxygen species and inhibiting muscle pyruvate kinase activity. This study aimed to investigate whether sarcopenic status in leprosy survivors was influenced by recent history of DDS medication.
Methods
Forty-one elderly female leprosy survivors were recruited. The DDS group was defined as survivors who had been taking the drug for the past year or more. Body composition measured by dual energy X-ray absorptiometry, limb muscle strength, short physical performance battery, and International Physical Activity Questionnaire in Korean were compared.
Results
The DDS group tended to have higher skeletal muscle mass index (24.4 ± 2.7 vs. 22.6 ± 2.2%, P = 0.066) and regional skeletal muscle mass index in non-dominant leg (8.9 ± 1.0 vs. 7.9 ± 0.9%, P = 0.018) than those of the control group although they had significantly worse leprosy disability than the control group (P  = 0.027). The DDS group had greater strength than the control group in non-dominant shoulder abductor, elbow flexor, hip flexor, and knee extensor (P = 0.005, P = 0.029, P = 0.021, and P = 0.002, respectively). Weekly walking amount was significantly longer (P  = 0.020) in the DDS group than the control group. The total lifetime DDS exposure significantly correlated with skeletal muscle mass of the lower extremity in non-dominant leg (r = 0.379, P = 0.015).
Conclusions
DDS-taking leprosy survivors had larger skeletal muscle mass and greater muscle strength over non-taking survivors. There was a dose–response relationship between total lifetime DDS exposure and skeletal muscle mass of lower extremity. These findings might suggest potential anti-sarcopenic effects of DDS.

 

Lee, S. Y., Kim, W., Park, H. -W., Park, S. C., Kim, I. K., and Chung, S. G. (2016) Anti-sarcopenic effects of diamino-diphenyl sulfone observed in elderly female leprosy survivors: a cross-sectional study. Journal of Cachexia, Sarcopenia and Muscle, 7: 322329. doi: 10.1002/jcsm.12074.

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     Page 330344

Amy Lewis, Jen Y. Lee, Anna V. Donaldson, Amanda Natanek, Srividya Vaidyanathan, William D.-C. Man, Nicholas S. Hopkinson, Avan A. Sayer, Harnish P. Patel, Cyrus Cooper, Holly Syddall, Michael I. Polkey, Paul R. Kemp

Increased expression of H19/miR-675 is associated with a low fat-free mass index in patients with COPDBackground
Loss of muscle mass and strength is a significant comorbidity in patients with chronic obstructive pulmonary disease (COPD) that limits their quality of life and has prognostic implications but does not affect everyone equally. To identify mechanisms that may contribute to the susceptibility to a low muscle mass, we investigated microRNA (miRNA) expression, methylation status, and regeneration in quadriceps muscle from COPD patients and the effect of miRNAs on myoblast proliferation in vitro. The relationships of miRNA expression with muscle mass and strength was also determined in a group of healthy older men.
Methods
We identified miRNAs associated with a low fat-free mass (FFM) phenotype in a small group of patients with COPD using a PCR screen of 750 miRNAs. The expression of two differentially expressed miRNAs (miR-675 and miR-519a) was determined in an expanded group of COPD patients and their associations with FFM and strength identified. The association of these miRNAs with FFM and strength was also explored in a group of healthy community-dwelling older men. As the expression of the miRNAs associated with FFM could be regulated by methylation, the relative methylation of the H19 ICR was determined. Furthermore, the proportion of myofibres with centralized nuclei, as a marker of muscle regeneration, in the muscle of COPD patients was identified by immunofluorescence.
Results
Imprinted miRNAs (miR-675 and from a cluster, C19MC which includes miR-519a) were differentially expressed in the quadriceps of patients with a low fat-free mass index (FFMI) compared to those with a normal FFMI. In larger cohorts, miR-675 and its host gene (H19) were higher in patients with a low FFMI and strength. The association of miR-519a expression with FFMI was present in male patients with severe COPD. Similar associations of miR expression with lean mass and strength were not observed in healthy community dwelling older men participating in the Hertfordshire Sarcopenia Study. Relative methylation of the H19 ICR was reduced in COPD patients with muscle weakness but was not associated with FFM. In vitro, miR-675 inhibited myoblast proliferation and patients with a low FFMI had fewer centralized nuclei suggesting miR-675 represses regeneration.
Conclusions
The data suggest that increased expression of miR-675/H19 and altered methylation of the H19 imprinting control region are associated with a low FFMI in patients with COPD but not in healthy community dwelling older men suggesting that epigenetic control of this loci may contribute to a susceptibility to a low FFMI.

 

Lewis, A., Lee, J. Y., Donaldson, A. V., Natanek, S. A., Vaidyanathan, S., Man, W. D.-C., Hopkinson, N. S., Sayer, A. A., Patel, H. P., Cooper, C., Syddall, H., Polkey, M. I., and Kemp, P. R. (2016) Increased expression of H19/miR-675 is associated with a low fat-free mass index in patients with COPD. Journal of Cachexia, Sarcopenia and Muscle, 7: 330344. doi: 10.1002/jcsm.12078.

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     Page 345354

Fabio Penna, Andrea Bonetto, Zaira Aversa, Valerio Giacomo Minero, Filippo Rossi Fanelli, Paola Costelli, Maurizio Muscaritoli

Effect of the specific proteasome inhibitor bortezomib on cancer-related muscle wastingBackground
Muscle wasting, a prominent feature of cancer cachexia, is mainly caused by sustained protein hypercatabolism. The enhanced muscle protein degradation rates rely on the activity of different proteolytic systems, although the Adenosine triphosphate (ATP)-ubiquitin-proteasome-dependent pathway and autophagy have been shown to play a pivotal role. Bortezomib is a potent reversible and selective proteasome and NF-κB inhibitor approved for the clinical use, which has been shown to be effective in preventing muscle wasting in different catabolic conditions. The aim of the present study has been to investigate whether pharmacological inhibition of proteasome by bortezomib may prevent skeletal muscle wasting in experimental cancer cachexia.
Methods
Cancer cachexia was induced in rats by intraperitoneal injection of Yoshida AH-130 ascites hepatoma cells and in mice by subcutaneous inoculation of C26 carcinoma cells. Animals were then further randomized to receive bortezomib. The AH-130 hosts were weighted and sacrificed under anaesthesia, on Days 3, 4, 5, and 7 after tumour inoculation, while C26-bearing mice were weighted and sacrificed under anaesthesia 12 days after tumour transplantation. NF-κB and proteasome activation, MuRF1 and atrogin-1 mRNA expression and beclin-1 protein levels were evaluated in the gastrocnemius of controls and AH-130 hosts.
Results
Bortezomib administration in the AH-130 hosts, although able to reduce proteasome and NF-κB DNA-binding activity in the skeletal muscle on Day 7 after tumour transplantation, did not prevent body weight loss and muscle wasting. In addition, bortezomib exerted a transient toxicity, as evidenced by the reduced food intake and by the increase in NF-κB DNA-binding activity in the AH-130 hosts 3 days after tumour transplantation. Beclin-1 protein levels were increased by bortezomib treatment in Day 3 controls but were unchanged on both Days 3 and 7 in the AH-130 hosts, suggesting that an early compensatory induction of autophagy may exist in healthy but not in tumour-bearing animals. Regarding C26-bearing mice, bortezomib did not prevent as well body and muscle weight loss 12 days after tumour implantation.
Conclusions
The results obtained suggest that proteasome inhibition by bortezomib is not able to prevent muscle wasting in experimental cancer cachexia. Further studies are needed to address the issue whether a different dosage of bortezomib alone or in combination with other drugs modulating different molecular pathways may effectively prevent muscle wasting during cancer cachexia.

 

Penna, F., Bonetto, A., Aversa, Z., Minero, V. G., Rossi Fanelli, F., Costelli, P., and Muscaritoli, M. (2016) Effect of the specific proteasome inhibitor bortezomib on cancer-related muscle wasting. Journal of Cachexia, Sarcopenia and Muscle, 7: 345354. doi: 10.1002/jcsm.12050.

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     Page 355365

Andrew J. Stewart Coats, Gwo Fuang Ho, Kumar Prabhash, Stephan von Haehling, Julia Tilson, Richard Brown, John Beadle, Stefan D. Anker and for and on behalf of the ACT-ONE study group

Espindolol for the treatment and prevention of cachexia in patients with stage III/IV non-small cell lung cancer or colorectal cancer: a randomized, double-blind, placebo-controlled, international multicentre phase II study (the ACT-ONE trial)Background
Cancer cachexia is a major cause of morbidity and mortality with no widely approved treatment.
Methods
The ACT-ONE trial is a randomized, double-blind, parallel group, placebo-controlled, phase II multicentre trial in patients (25-80 years) with stages III or IV colorectal cancer or non-small cell lung cancer-related cachexia that tested two doses of espindolol (a novel non-selective β blocker with central 5-HT1a and partial β2 receptor agonist effects). The primary endpoint was the difference in the rate of weight change over 16 weeks (linear mixed-effect model for repeated measures) between high-dose espindolol and placebo.
Results
Eighty-seven patients were randomized centrally in blocks in a ratio 3:2:1 [42 high dose, 10 mg twice daily (bd):31 placebo:14 low dose, 2.5 mg bd]. High-dose espindolol produced a statistically and clinically significant weight gain (+0.54 kg/4 weeks, 95% CI 0.38–0.70) compared with a weight loss on placebo (−0.21 kg/4 weeks, 95% CI -0.37–0.05); P < 0.0001. High-dose espindolol produced a statistically significant increase in lean body mass, whilst changes in fat mass were neutral. Hand grip strength significantly (high dose −1.15 ± 0.7 kg, placebo −3.51 ± 0.8 kg change per 4 weeks; P = 0.0134), stair climbing power, and 6-min walk test non-significantly were all directionally in favour of high-dose espindolol. There were no clinically significant differences in safety signals or survival between treatment groups, although a numerical excess of dyspnoea was seen with high-dose espindolol (19.1%) compared with placebo (3.2%).
Conclusions
This positive trial showed that espindolol 10 mg bd significantly reversed weight loss, improved fat free mass, and maintained fat mass in advanced colorectal cancer and non-small cell lung cancer-related cachexia. This was associated with a significant improvement in handgrip strength, supporting the further investigation of 10 mg bd espindolol for the treatment of cancer cachexia. Although not powered to look at dose response, most treatment effects for low dose lay between high dose and placebo, suggesting that there may be a dose response in the effects of espindolol.

 

 

Stewart Coats, A. J., Ho, G. F., Prabhash, K., von Haehling, S., Tilson, J., Brown, R., Beadle, J., Anker, S. D., and for and on behalf of the ACT-ONE study group (2016) Espindolol for the treatment and prevention of cachexia in patients with stage III/IV non-small cell lung cancer or colorectal cancer: a randomized, double-blind, placebo-controlled, international multicentre phase II study (the ACT-ONE trial). Journal of Cachexia, Sarcopenia and Muscle, 7: 355365. doi: 10.1002/jcsm.12126.

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     Page 366376

Yuko Iwata, Nobuyuki Suzuki, Hitomi Ohtake, Shinya Kamauchi, Naohiro Hashimoto, Tohru Kiyono, Shigeo Wakabayashi

Cancer cachexia causes skeletal muscle damage via transient receptor potential vanilloid 2-independent mechanisms, unlike muscular dystrophyBackground
Muscle wasting during cancer cachexia contributes to patient morbidity. Cachexia-induced muscle damage may be understood by comparing its symptoms with those of other skeletal muscle diseases, but currently available data are limited.
Methods
We modelled cancer cachexia in mice bearing Lewis lung carcinoma/colon adenocarcinoma and compared the associated muscle damage with that in a murine muscular dystrophy model (mdx mice). We measured biochemical and immunochemical parameters: amounts/localization of cytoskeletal proteins and/or Ca2+ signalling proteins related to muscle function and abnormality. We analysed intracellular Ca2+ mobilization and compared results between the two models. Involvement of Ca2+-permeable channel transient receptor potential vanilloid 2 (TRPV2) was examined by inoculating Lewis lung carcinoma cells into transgenic mice expressing dominant-negative TRPV2.
Results
Tumourigenesis caused loss of body and skeletal muscle weight and reduced muscle force and locomotor activity. Similar to mdx mice, cachexia muscles exhibited myolysis, reduced sarcolemmal sialic acid content, and enhanced lysosomal exocytosis and sarcolemmal localization of phosphorylated Ca2+/CaMKII. Abnormal autophagy and degradation of dystrophin also occurred. Unlike mdx muscles, cachexia muscles did not exhibit regeneration markers (centrally nucleated fibres), and levels of autophagic proteolytic pathway markers increased. While a slight accumulation of TRPV2 was observed in cachexia muscles, Ca2+ influx via TRPV2 was not elevated in cachexia-associated myotubes, and the course of cachexia pathology was not ameliorated by dominant-negative inhibition of TRPV2.
Conclusions
Thus, cancer cachexia may induce muscle damage through TRPV2-independent mechanisms distinct from those in muscular dystrophy; this may help treat patients with tumour-induced muscle wasting.

 

 

Iwata, Y., Suzuki, N., Ohtake, H., Kamauchi, S., Hashimoto, N., Kiyono, T., and Wakabayashi, S. (2016) Cancer cachexia causes skeletal muscle damage via transient receptor potential vanilloid 2-independent mechanisms, unlike muscular dystrophy. Journal of Cachexia, Sarcopenia and Muscle, 7: 366376. doi: 10.1002/jcsm.12067.

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     Page 377387

Cécile Polge, Roza Leulmi, Marianne Jarzaguet, Agnes Claustre1, Lydie Combaret, Daniel Béchet, Anne-Elisabeth Heng, Didier Attaix, Daniel Taillandier

UBE2B is implicated in myofibrillar protein loss in catabolic C2C12 myotubesBackground
Skeletal muscle protein loss is an adaptive response to various patho-physiological situations, and the ubiquitin proteasome system (UPS) is responsible for the degradation of the bulk of muscle proteins. The role of E2 ubiquitin-conjugating enzymes is still poorly understood in skeletal muscle.
Methods
We screened for E2s expression levels in C2C12 myotubes submitted to the catabolic glucocorticoid dexamethasone (Dex).
Results
One micromolar Dex induced an accumulation of proteasome substrates (polyUb conjugates) and an overexpression of the muscle-specific E3 ligase MuRF1 and of six E2 enzymes, UBE2A, UBE2B, UBE2D1, UBE2D2, UBE2G1, and UBE2J1. However, only MuRF1 and UBE2B were sensitive to mild catabolic conditions (0.16 μM Dex). UBE2B knockdown induced a sharp decrease of total (−18%) and K48 (−28%) Ub conjugates, that is, proteasome substrates, indicating an important role of UBE2B in the overall protein breakdown in catabolic myotubes.
Conclusions
Interestingly, these results indicate an important role of UBE2B on muscle protein homeostasis during catabolic conditions.

 

Polge, C., Leulmi, R., Jarzaguet, M., Claustre, A., Combaret, L., Béchet, D., Heng, A. -E., Attaix, D., and Taillandier, D. (2016) UBE2B is implicated in myofibrillar protein loss in catabolic C2C12 myotubes. Journal of Cachexia, Sarcopenia and Muscle, 7: 377387. doi: 10.1002/jcsm.12060.

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Number 4 / August 2017

 

     Page 523–526

John E. Morley

Anorexia of ageing: a key component in the pathogenesis of both sarcopenia and cachexiaThe anorexia of aging was first recognized as a physiological syndrome 30 years ago. Its major causes are an alteration in fundal compliance with an increase in antral stretch and enhanced cholecystokinin activity leading to increased satiation.This anorexia leads to weight loss in aging persons and is one of the component causes of the aging related sarcopenia. This physiological anorexia also increases the risk of more severe anorexia when an older person has an increase in inflammatory cytokines such as occurs when they have an illness. This results in an increase in the anorexia due to cachexia in older persons.

 

Morley, J. E. (2017) Anorexia of ageing: a key component in the pathogenesis of both sarcopenia and cachexia. Journal of Cachexia, Sarcopenia and Muscle, 8: 523–526. doi: 10.1002/jcsm.12192.

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     Page 527–528

Vickie E. Baracos

Psoas as a sentinel muscle for sarcopenia: a flawed premiseno abstract

 

Baracos, V. E. (2017) Psoas as a sentinel muscle for sarcopenia: a flawed premise. Journal of Cachexia, Sarcopenia and Muscle, 8: 527–528. doi: 10.1002/jcsm.12221.
Author Information

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     Page 529–541

Milan Holecek

Beta-hydroxy-beta-methylbutyrate supplementation and skeletal muscle in healthy, muscle-wasting conditionsBeta-hydroxy-beta-methylbutyrate (HMB) is a metabolite of the essential amino acid leucine that has been reported to have anabolic effects on protein metabolism. The aims of this article were to summarize the results of studies of the effects of HMB on skeletal muscle and to examine the evidence for the rationale to use HMB as a nutritional supplement to exert beneficial effects on muscle mass and function in various conditions of health and disease.
The data presented here indicate that the beneficial effects of HMB have been well characterized in strength-power and endurance exercise. HMB attenuates exercise-induced muscle damage and enhances muscle hypertrophy and strength, aerobic performance, resistance to fatigue, and regenerative capacity. HMB is particularly effective in untrained individuals who are exposed to strenuous exercise and in trained individuals who are exposed to periods of high physical stress. The low effectiveness of HMB in strength-trained athletes could be due to the suppression of the proteolysis that is induced by the adaptation to training, which may blunt the effects of HMB. Studies performed with older people have demonstrated that HMB can attenuate the development of sarcopenia in elderly subjects and that the optimal effects of HMB on muscle growth and strength occur when it is combined with exercise. Studies performed under in vitro conditions and in various animal models suggest that HMB may be effective in treatment of muscle wasting in various forms of cachexia. However, there are few clinical reports of the effects of HMB on muscle wasting in cachexia; in addition, most of these studies evaluated the therapeutic potential of combinations of various agents. Therefore, it has not been possible to determine whether HMB was effective or if there was a synergistic effect. Although most of the endogenous HMB is produced in the liver, there are no reports regarding the levels and the effects of HMB supplementation in subjects with liver disease. Several studies have suggested that anabolic effects of HMB supplementation on skeletal muscle do not occur in healthy, non-exercising subjects.
It is concluded that (i) HMB may be applied to enhance increases in the mass and strength of skeletal muscles in subjects who exercise and in the elderly and (ii) studies examining the effects of HMB administered alone are needed to obtain conclusions regarding the specific effectiveness in attenuating muscle wasting in various muscle-wasting disorders.

 

Holecek, M. (2017) Beta-hydroxy-beta-methylbutyrate supplementation and skeletal muscle in healthy and muscle-wasting conditions. Journal of Cachexia, Sarcopenia and Muscle, 8: 529–541. doi: 10.1002/jcsm.12208.

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     Page 542–548

Marjan Hajahmadi, Sara Shemshadi, Ehsan Khalilipur, Ahmad Amin, Sepideh Taghavi, Majid Maleki, Hadi Malek, Nasim Nader

Muscle wasting in young patients with dilated cardiomyopathyBackground
Muscle wasting can be accelerated by chronic diseases such as heart failure and is one of the major causes of disability, morbidity, and mortality in this population. We aimed to investigate the incidence of muscle wasting and its associated factors in dilated cardiomyopathy patients younger than 55 years of age.
Methods
Between April 2014 and December 2015, all symptomatic patients with a diagnosis of non-ischaemic dilated cardiomyopathy who were referred to heart failure clinic were included in our study.
Dual energy X-ray absorptiometry was used to evaluate body composition and identify muscle wasting. Muscle mass was calculated as the ratio of an individual's total lean mass of legs and arms (also called appendicular skeletal muscle) to their squared height (kg/m2). The muscle mass values of less than 5.45 kg/m2 for women and 7.26 kg/m2 for men were considered low.
Results
A total of 55 patients (32 male) were included. The mean (standard deviation) of age was 37.3 (10.1) years, and the mean of left ventricular ejection fraction was 21.4%. Most of the patients were in the New York Heart Association classes of II and II–III. Twenty-six patients (47.3%) met criteria for muscle wasting. Patients with muscle wasting had lower left ventricular ejection fraction, lower 6-min walk distance, and higher New York Heart Association function class and hospitalization rate.
Conclusions
We concluded that muscle wasting might be present in younger patients with heart failure, particularly in those who are in worse clinical condition.

 

Hajahmadi, M., Shemshadi, S., Khalilipur, E., Amin, A., Taghavi, S., Maleki, M., Malek, H., and Naderi, N. (2017) Muscle wasting in young patients with dilated cardiomyopathy. Journal of Cachexia, Sarcopenia and Muscle, 542–548. doi: 10.1002/jcsm.12193.

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     Page 549–556

Andrew L. Clark, Andrew J.S. Coats, Henry Krum4, Hugo A. Katus, Paul Mohacsi, Damien Salekin, Melissa K. Schultz, Milton Packer, Stefan D. Anker

Effect of beta-adrenergic blockade with carvedilol on cachexia in severe chronic heart failure: results from the COPERNICUS trialBackground
Cardiac cachexia frequently accompanies the progression of heart failure despite the use of effective therapies for left ventricular dysfunction. Activation of the sympathetic nervous system has been implicated in the pathogenesis of weight loss, but the effects of sympathetic antagonism on cachexia are not well defined.
Methods
We prospectively evaluated changes in body weight in 2289 patients with heart failure who had dyspnoea at rest or on minimal exertion and a left ventricular ejection fraction <25%. Patients were randomly assigned (double-blind) to receive either placebo (n = 1133) or carvedilol (n = 1156) and were followed for the occurrence of major clinical events for up to 29 months (COPERNICUS trial). Patients were not enrolled if they had signs of clinically significant fluid retention due to heart failure.
Results
Patients in the carvedilol group were 33% less likely than patients in the placebo group to experience a further significant loss of weight (>6%) (95% confidence interval: 14–48%, P = 0.002) and were 37% more likely to experience a significant gain in weight (=5%) (95% confidence interval: 12–66%, P = 0.002). Carvedilol's ability to prevent weight loss was most marked in patients with increased body mass index at baseline, whereas its ability to promote weight gain was most marked in patients with decreased body mass index at baseline. Increases in weight were not accompanied by evidence of fluid retention. Baseline values for body mass index and change in body weight were significant predictors of survival regardless of treatment.
Conclusions
Carvedilol attenuated the development and promoted a partial reversal of cachexia in patients with severe chronic heart failure, supporting a role for prolonged sympathetic activation in the genesis of weight loss.

 

Clark, A. L., Coats, A. J. S., Krum, H., Katus, H. A., Mohacsi, P., Salekin, D., Schultz, M. K., Packer, M., and Anker, S. D. (2017) Effect of beta-adrenergic blockade with carvedilol on cachexia in severe chronic heart failure: results from the COPERNICUS trial. Journal of Cachexia, Sarcopenia and Muscle, 8: 549–556. doi: 10.1002/jcsm.12191.

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     Page 557–566

Katsuhiko Kohara, Yoko Okada, Masayuki Ochi, Maya Ohara, Tokihisa Nagai, Yasuharu Tabara, Michiya Igase

Muscle mass decline, arterial stiffness, white matter hyperintensity, and cognitive impairment: Japan Shimanami Health Promoting Program studyBackground
There is a close association between frailty and cognitive impairment. However, the underlying contribution of sarcopenia to the development of cognitive impairment is unclear. We investigated the possible association between muscle mass decline and cognitive impairment in a cross-sectional study of 1518 subjects aged 55 years or above. We also evaluated arterial stiffness and white matter hyperintensities (WMHs) as possible underlying mechanisms for this association.
Methods
Two sarcopenic indices were measured: thigh muscle cross-sectional area (CSA; calculated by computed tomography) and skeletal muscle mass (bioelectric impedance). Muscle mass decline was defined as either the bottom 10% or 20% of participants for each sex. Cognitive function was assessed using the Touch Panel-type Dementia Assessment Scale, and brachial–ankle pulse wave velocity was measured as an index of arterial stiffness.
Results
Both sarcopenic indices were modestly but significantly associated with brachial–ankle pulse wave velocity in male and female subjects. The presence of WMHs was significantly associated with low thigh muscle CSA in men and with low skeletal muscle mass in women. The Touch Panel-type Dementia Assessment Scale score was modestly but significantly and positively associated with thigh muscle CSA in men and skeletal muscle mass in women. Muscle mass decline in the bottom 10% of participants on both sarcopenic indices was significantly and independently related to cognitive impairment in women.
Conclusions
Lower sarcopenic indices are significantly related to lower cognitive scores. Arterial stiffness and WMHs could account, at least in part, for this association.

 

 

Kohara, K., Okada, Y., Ochi, M., Ohara, M., Nagai, T., Tabara, Y., and Igase, M. (2017) Muscle mass decline, arterial stiffness, white matter hyperintensity, and cognitive impairment: Japan Shimanami Health Promoting Program study. Journal of Cachexia, Sarcopenia and Muscle, 8: 557–566. doi: 10.1002/jcsm.12195.

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     Page 567–582

H. Alexander Ebhardt, Simone Degen, Valentina Tadini, Alain Schilb, Neil Johns, Carolyn A. Greig, Kenneth C.H. Fearon, Ruedi Aebersold, Carsten Jacobi

Comprehensive proteome analysis of human skeletal muscle in cachexia and sarcopenia: A pilot studyBackground
Cancer cachexia (cancer-induced muscle wasting) is found in a subgroup of cancer patients leaving the patients with a poor prognosis for survival due to a lower tolerance of the chemotherapeutic drug. The cause of the muscle wasting in these patients is not fully understood, and no predictive biomarker exists to identify these patients early on. Skeletal muscle loss is an inevitable consequence of advancing age. As cancer frequently occurs in old age, identifying and differentiating the molecular mechanisms mediating muscle wasting in cancer cachexia vs. age-related sarcopenia are a challenge. However, the ability to distinguish between them is critical for early intervention, and simple measures of body weight may not be sufficiently sensitive to detect cachexia early.
Methods
We used a range of omics approaches: (i) undepleted proteome was quantified using advanced high mass accuracy mass spectrometers in SWATH-MS acquisition mode; (ii) phospho epitopes were quantified using protein arrays; and (iii) morphology was assessed using fluorescent microscopy.
Results
We quantified the soluble proteome of muscle biopsies from cancer cachexia patients and compared them with cohorts of cancer patients and healthy individuals with and without age-related muscle loss (aka age-related sarcopenia). Comparing the proteomes of these cohorts, we quantified changes in muscle contractile myosins and energy metabolism allowing for a clear identification of cachexia patients. In an in vitro time lapse experiment, we mimicked cancer cachexia and identified signal transduction pathways governing cell fusion to play a pivotal role in preventing muscle regeneration.
Conclusions
The work presented here lays the foundation for further understanding of muscle wasting diseases and holds the promise of overcoming ambiguous weight loss as a measure for defining cachexia to be replaced by a precise protein signature.

 

Ebhardt, H. A., Degen, S., Tadini, V., Schilb, A., Johns, N., Greig, C. A., Fearon, K. C. H., Aebersold, R., and Jacobi, C. (2017) Comprehensive proteome analysis of human skeletal muscle in cachexia and sarcopenia: A pilot study. Journal of Cachexia, Sarcopenia and Muscle, 8: 567–582. doi: 10.1002/jcsm.12188.

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     Page 583–597

Julie Rodriguez, Nicolas Pierre, Damien Naslain, Françoise Bontemps, Daneel Ferreira, Fabian Priem, Louise Deldicque, Marc Francaux

Urolithin B, a newly identified regulator of skeletal muscle massBackground
The control of muscle size is an essential feature of health. Indeed, skeletal muscle atrophy leads to reduced strength, poor quality of life, and metabolic disturbances. Consequently, strategies aiming to attenuate muscle wasting and to promote muscle growth during various (pathological) physiological states like sarcopenia, immobilization, malnutrition, or cachexia are needed to address this extensive health issue. In this study, we tested the effects of urolithin B, an ellagitannin-derived metabolite, on skeletal muscle growth.
Methods
C2C12 myotubes were treated with 15 μM of urolithin B for 24 h. For in vivo experiments, mice were implanted with mini-osmotic pumps delivering continuously 10 μg/day of urolithin B during 28 days. Muscle atrophy was studied in mice with a sciatic nerve denervation receiving urolithin B by the same way.
Results
Our experiments reveal that urolithin B enhances the growth and differentiation of C2C12 myotubes by increasing protein synthesis and repressing the ubiquitin–proteasome pathway. Genetic and pharmacological arguments support an implication of the androgen receptor. Signalling analyses suggest a crosstalk between the androgen receptor and the mTORC1 pathway, possibly via AMPK. In vivo experiments confirm that urolithin B induces muscle hypertrophy in mice and reduces muscle atrophy after the sciatic nerve section.
Conclusions
This study highlights the potential usefulness of urolithin B for the treatment of muscle mass loss associated with various (pathological) physiological states.

 

Rodriguez, J., Pierre, N., Naslain, D., Bontemps, F., Ferreira, D., Priem, F., Deldicque, L., and Francaux, M. (2017) Urolithin B, a newly identified regulator of skeletal muscle mass. Journal of Cachexia, Sarcopenia and Muscle, 8: 583–597. doi: 10.1002/jcsm.12190.

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     Page 598–606

Ayse Zengin, Stephen R. Pye, Michael J. Cook, Judith E. Adams, Rainer Rawer, Frederick C.W. Wu, Terence W. O'Neill, Kate A. Ward

Associations of muscle force, power, cross-sectional muscle area and bone geometry in older UK menBackground
Ageing is associated with sarcopenia, osteoporosis, and increased fall risk, all of which contribute to increased fracture risk. Mechanically, bone strength adapts in response to forces created by muscle contractions. Adaptations can be through changes in bone size, geometry, and bending strength. Muscle mass is often used as a surrogate for muscle force; however, force can be increased without changes in muscle mass. Increased fall risk with ageing has been associated with a decline in muscle power—which is a measure of mobility. The aims of this study were as follows: (i) to investigate the relationship between muscle parameters in the upper and lower limbs with age in UK men and the influence of ethnicity on these relationships; (ii) to examine the relationships between jump force/grip strength/cross-sectional muscle area (CSMA) with bone outcomes at the radius and tibia.
Methods
White European, Black Afro-Caribbean, and South Asian men aged 40–79 years were recruited from Manchester, UK. Cortical bone mineral content, cross-sectional area, cortical area, cross-sectional moment of inertia, and CSMA were measured at the diaphysis of the radius and tibia using peripheral quantitative computed tomography. Lower limb jump force and power were measured from a single two-legged jump performed on a ground-reaction force platform. Grip strength was measured using a dynamometer. Associations between muscle and bone outcomes was determined using linear regression with adjustments for age, height, weight, and ethnicity.
Results
Three hundred and one men were recruited. Jump force was negatively associated with age; for every 10 year increase in age, there was a 4% reduction in jump force (P < 0.0001). There was a significant age–ethnicity interaction for jump power (P = 0.039); after adjustments, this was attenuated (P = 0.088). For every 10 year increase in age, grip strength decreased by 11%. Jump force was positively associated with tibial bone outcomes: a 1 standard deviation greater jump force was associated with significantly higher cortical bone mineral content 3.1%, cross-sectional area 4.2%, cortical area 3.4%, and cross-sectional moment of inertia 6.8% (all P < 0.001). Cross-sectional muscle area of the lower leg was not associated with tibial bone outcomes. Both grip strength and CSMA of the arm were positively associated, to a similar extent, with radius diaphyseal bone outcomes.
Conclusions
Jump force and power are negatively associated with age in UK men. In the lower limb, the measurement of jump force is more strongly related to bone outcomes than CSMA. It is important to consider jump force and power when understanding the aetiology of bone loss and mobility in ageing men.

 

Zengin, A., Pye, S. R., Cook, M. J., Adams, J. E., Rawer, R., Wu, F. C. W., O'Neill, T. W., and Ward, K. A. (2017) Associations of muscle force, power, cross-sectional muscle area and bone geometry in older UK men. Journal of Cachexia, Sarcopenia and Muscle, 8: 598–606. doi: 10.1002/jcsm.12198.

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     Page 607–614

Hyuma Makizako, Hiroyuki Shimada, Takehiko Doi, Kota Tsutsumimoto, Sangyoon Lee, Sung Chul Lee, Kazuhiro Harada, Ryo Hotta, Sho Nakakubo, Seongryu Bae1, Kenji Harada, Daisuke Yoshida, Kazuki Uemura, Yuya Anan, Hyuntae Park, Takao Suzuki

Age-dependent changes in physical performance and body composition in community-dwelling Japanese older adultsBackground
The aim of this study was to describe the age-dependent changes in the parameters of physical performance and body composition in Japanese older adults who are independently dwelling in the community. We also examined whether the age-dependent changes differ among physical performance and body composition parameters.
Methods
Cross-sectional data from 10 092 community-dwelling older adults (mean age 73.6 years; 5296 women) were analyzed. The measures of physical performance included hand-grip strength, the five-times-sit-to-stand test, and walking speed. Body composition parameters (body weight, fat mass, and appendicular skeletal muscle mass) were measured with a bioelectrical impedance analyser. Correlations between age and the physical performance and body composition parameters were tested. The T-scores of physical performance and body composition measurements were calculated and presented according to 5-year age groups to examine the differences in age-dependent changes in physical performance and body composition parameters.
Results
All physical performance measures significantly decreased with aging. The cumulative mean T-scores according to age group showed different age-dependent changes between body mass index (BMI) and appendicular skeletal muscle mass index (ASMI) (cumulative mean T-score change of BMI and ASMI of -5.7 to -2.9 and -12.7 to -12.1, respectively). The slope declines in age-associated changes were greater in grip strength (ß = -0.77, 95% confidence interval = -0.82 to -0.76) for men and in walking speed (ß = -0.95, 95% confidence interval = -0.99 to -0.90) for women.
Conclusions
The patterns of age-dependent decreases in physical performance measures differed among parameters and between sexes. There is a possibility of a difference in the age-related slope patterns among parameters; decreases in grip strength in men and walking speed in women may be more prominent with advancing age. Furthermore, the decrease in ASMI with age is more striking than that of BMI.

 

Makizako, H., Shimada, H., Doi, T., Tsutsumimoto, K., Lee, S., Lee, S. C., Harada, K., Hotta, R., Nakakubo, S., Bae, S., Harada, K., Yoshida, D., Uemura, K., Anan, Y., Park, H., and Suzuki, T. (2017) Age-dependent changes in physical performance and body composition in community-dwelling Japanese older adults. Journal of Cachexia, Sarcopenia and Muscle, 8: 607–614. doi: 10.1002/jcsm.12197.

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     Page 615–622

Susanne Blauwhoff-Buskermolen, Jacqueline A.E. Langius, Annemarie Becker, Henk M.W. Verheul, Marian A.E. de van der Schueren

The influence of different muscle mass measurements on the diagnosis of cancer cachexiaBackground
Progressive loss of muscle mass is a major characteristic of cancer cachexia. Consensus definitions for cachexia provide different options to measure muscle mass. This study describes the effect of different methods to determine muscle mass on the diagnosis of cancer cachexia. In addition, the association of cachexia with other features of cachexia, quality of life, and survival was explored.
Methods
Prior to chemotherapy, cachexia was assessed by weight loss, body mass index, and muscle mass measurements, the latter by mid-upper arm muscle area (MUAMA), computed tomography (CT) scans, and bio-electrical impedance analysis (BIA). In addition, appetite, inflammation, muscle strength, fatigue, quality of life, and survival were measured, and associations with cachexia were explored.
Results
Included were 241 patients with advanced cancer of the lung (36%), colon/rectum (31%), prostate (18%), or breast (15%). Mean age was 64 ± 10 years; 54% was male. Prevalence of low muscle mass was as follows: 13% with MUAMA, 59% with CT, and 93% with BIA. In turn, the prevalence of cachexia was 37, 43, and 48%, whereby weight loss >5% was the most prominent component of being defined cachectic. Irrespective of type of muscle measurement, patients with cachexia presented more often with anorexia, inflammation, low muscle strength, and fatigue and had lower quality of life. Patients with cachexia had worse overall survival compared with patients without cachexia: HRs 2.00 (1.42–2.83) with MUAMA, 1.64 (1.15–2.34) with CT, and 1.50 (1.05–2.14) with BIA.
Conclusions
Although the prevalence of low muscle mass in patients with cancer depended largely on the type of muscle measurement, this had little influence on the diagnosis of cancer cachexia (as the majority of patients was already defined cachectic based on weight loss). New studies are warranted to further elucidate the additional role of muscle measurements in the diagnosis of cachexia and the association with clinical outcomes.

 

Blauwhoff-Buskermolen, S., Langius, J. A. E., Becker, A., Verheul, H. M. W., and de van der Schueren, M. A. E. (2017) The influence of different muscle mass measurements on the diagnosis of cancer cachexia. Journal of Cachexia, Sarcopenia and Muscle, 8: 615–622. doi: 10.1002/jcsm.12200.

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     Page 623–629

Elisabeth C.W. Neefjes, Renske M. van den Hurk, Susanne Blauwhoff-Buskermolen, Maurice J.D.L. van der Vorst, Annemarie Becker-Commissaris, Marian A.E. de van der Schueren, Laurien M. Buffart, Henk M.W. Verheul

Muscle mass as a target to reduce fatigue in patients with advanced cancerBackground
Cancer-related fatigue (CRF) reduces quality of life and the activity level of patients with cancer. Cancer related fatigue can be reduced by exercise interventions that may concurrently increase muscle mass. We hypothesized that low muscle mass is directly related to higher CRF.
Methods
A total of 233 patients with advanced cancer starting palliative chemotherapy for lung, colorectal, breast, or prostate cancer were studied. The skeletal muscle index (SMI) was calculated as the patient's muscle mass on level L3 or T4 of a computed tomography scan, adjusted for height. Fatigue was assessed with the Functional Assessment of Chronic Illness Therapy-fatigue questionnaire (cut-off for fatigue <34). Multiple linear regression analyses were conducted to study the association between SMI and CRF adjusting for relevant confounders.
Results
In this group of patients with advanced cancer, the median fatigue score was 36 (interquartile range 26–44). A higher SMI on level L3 was significantly associated with less CRF for men (B 0.447, P 0.004) but not for women (B − 0.401, P 0.090). No association between SMI on level T4 and the Functional Assessment of Chronic Illness Therapy-fatigue score was found (n = 82).
Conclusions
The association between SMI and CRF may lead to the suggestion that male patients may be able to reduce fatigue by exercise interventions aiming at an increased muscle mass. In women with advanced cancer, CRF is more influenced by other causes, because it is not significantly related to muscle mass. To further reduce CRF in both men and women with cancer, multifactorial assessments need to be performed in order to develop effective treatment strategies.

 

Neefjes, E. C. W., van den Hurk, R. M., Blauwhoff-Buskermolen, S., van der Vorst, M. J. D. L., Becker-Commissaris, A., de van der Schueren, M. A. E., Buffart, L. M., and Verheul, H. M. W. (2017) Muscle mass as a target to reduce fatigue in patients with advanced cancer. Journal of Cachexia, Sarcopenia and Muscle, 8: 623–629. doi: 10.1002/jcsm.12199.

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     Page 630–638

Iris J.G. Rutten, Jorne Ubachs, Roy F.P.M. Kruitwagen, Regina G.H. Beets-Tan, Steven W.M. Olde Damink, Toon Van Gorp

Psoas muscle area is not representative of total skeletal muscle area in the assessment of sarcopenia in ovarian cancerBackground
Computed tomography measurements of total skeletal muscle area can detect changes and predict overall survival (OS) in patients with advanced ovarian cancer. This study investigates whether assessment of psoas muscle area reflects total muscle area and can be used to assess sarcopenia in ovarian cancer patients.
Methods
Ovarian cancer patients (n = 150) treated with induction chemotherapy and interval debulking were enrolled retrospectively in this longitudinal study. Muscle was measured cross sectionally with computed tomography in three ways: (i) software quantification of total skeletal muscle area (SMA); (ii) software quantification of psoas muscle area (PA); and (iii) manual measurement of length and width of the psoas muscle to derive the psoas surface area (PLW). Pearson correlation between the different methods was studied. Patients were divided into two groups based on the extent of change in muscle area, and agreement was measured with kappa coefficients. Cox-regression was used to test predictors for OS.
Results
Correlation between SMA and both psoas muscle area measurements was poor (r = 0.52 and 0.39 for PA and PLW, respectively). After categorizing patients into muscle loss or gain, kappa agreement was also poor for all comparisons (all ? < 0.40). In regression analysis, SMA loss was predictive of poor OS (hazard ratio 1.698 (95%CI 1.038–2.778), P = 0.035). No relationship with OS was seen for PA or PLW loss.
Conclusions
Change in psoas muscle area is not representative of total muscle area change and should not be used to substitute total skeletal muscle to predict survival in patients with ovarian cancer.

 

Rutten, I. J. G., Ubachs, J., Kruitwagen, R. F. P. M., Beets-Tan, R. G. H., Olde Damink, S. W. M., and Van Gorp, T. (2017) Psoas muscle area is not representative of total skeletal muscle area in the assessment of sarcopenia in ovarian cancer. Journal of Cachexia, Sarcopenia and Muscle, 8: 630–638. doi: 10.1002/jcsm.12180.

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     Page 639–646

Anne Tournadre, Bruno Pereira, Fréderic Dutheil, Charlotte Giraud, Daniel Courteix, Vincent Sapin, Thomas Frayssac, Sylvain Mathieu, Sandrine Malochet-Guinamand, Martin Soubrier

Changes in body composition and metabolic profile during interleukin 6 inhibition in rheumatoid arthritisBackground
Rheumatoid arthritis (RA) is a chronic inflammatory disease characterized by increased mortality associated with cardiometabolic disorders including dyslipidaemia, insulin resistance, and cachectic obesity. Tumour necrosis factor inhibitors and interleukin 6 receptor blocker licensed for the treatment of RA decrease inflammation and could thus improve cardiovascular risk, but their effects on body composition and metabolic profile need to be clarified. We investigated the effects of tocilizumab (TCZ), a humanized anti-interleukin 6 receptor antibody, on body composition and metabolic profile in patients treated for RA.
Methods
Twenty-one active RA patients treated with TCZ were included in a 1 year open follow-up study. Waist circumference, body mass index, blood pressure, lipid profile, fasting glucose, insulin, serum levels of adipokines and pancreatic/gastrointestinal hormones, and body composition (dual-energy X-ray absorptiometry) were measured at baseline and 6 and 12 months of treatment. At baseline, RA patients were compared with 21 non-RA controls matched for age, sex, body mass index, and metabolic syndrome.
Results
Compared with controls, body composition was altered in RA with a decrease in total and appendicular lean mass, whereas fat composition was not modified. Among RA patients, 28.6% had a skeletal muscle mass index below the cut-off point for sarcopaenia (4.8% of controls). After 1 year of treatment with TCZ, there was a significant weight gain without changes for fat mass. In contrast, an increase in lean mass was observed with a significant gain in appendicular lean mass and skeletal muscle mass index between 6 and 12 months. Distribution of the fat was modified with a decrease in trunk/peripheral fat ratio and an increase in subcutaneous adipose tissue. No changes for waist circumference, blood pressure, fasting glucose, and atherogenic index were observed.
Conclusions
Despite weight gain during treatment with TCZ, no increase in fat but a modification in fat distribution was observed. In contrast, muscle gain suggests that blocking IL-6 might be efficient in treating sarcopaenia associated with RA.

 

Tournadre, A., Pereira, B., Dutheil, F., Giraud, C., Courteix, D., Sapin, V., Frayssac, T., Mathieu, S., Malochet-Guinamand, S., and Soubrier, M. (2017) Changes in body composition and metabolic profile during interleukin 6 inhibition in rheumatoid arthritis. Journal of Cachexia, Sarcopenia and Muscle, 8: 639–646. doi: 10.1002/jcsm.12189.

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     Page 647–659

Yoann Barnouin, Jamie S. McPhee, Gillian Butler-Browne, Alessandra Bosutti, Giuseppe De Vito, David A. Jones, Marco Narici, Anthony Behin, Jean-Yves Hogrel, Hans Degens

Coupling between skeletal muscle fiber size and capillarization is maintained during healthy agingBackground
As muscle capillarization is related to the oxidative capacity of the muscle and the size of muscle fibres, capillary rarefaction may contribute to sarcopenia and functional impairment in older adults. Therefore, it is important to assess how ageing affects muscle capillarization and the interrelationship between fibre capillary supply with the oxidative capacity and size of the fibres.
Methods
Muscle biopsies from healthy recreationally active young (22 years; 14 men and 5 women) and older (74 years; 22 men and 6 women) people were assessed for muscle capillarization and the distribution of capillaries with the method of capillary domains. Oxidative capacity of muscle fibres was assessed with quantitative histochemistry for succinate dehydrogenase (SDH) activity.
Results
There was no significant age-related reduction in muscle fibre oxidative capacity. Despite 18% type II fibre atrophy (P = 0.019) and 23% fewer capillaries per fibre (P < 0.002) in the old people, there was no significant difference in capillary distribution between young and old people, irrespective of sex. The capillary supply to a fibre was primarily determined by fibre size and only to a small extent by oxidative capacity, irrespective of age and sex. Based on SDH, the maximal oxygen consumption supported by a capillary did not differ significantly between young and old people.
Conclusions
The similar quantitative and qualitative distribution of capillaries within muscle from healthy recreationally active older people and young adults indicates that the age-related capillary rarefaction, which does occur, nevertheless maintains the coupling between skeletal muscle fibre size and capillarization during healthy ageing.

 

Barnouin, Y., McPhee, J. S., Butler-Browne, G., Bosutti, A., De Vito, G., Jones, D. A., Narici, M., Behin, A., Hogrel, J.-Y., and Degens, H. (2017) Coupling between skeletal muscle fiber size and capillarization is maintained during healthy aging. Journal of Cachexia, Sarcopenia and Muscle, 8: 647–659. doi: 10.1002/jcsm.12194.

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     Page 660–672

Susann Lehmann, Joseph J. Bass, Thomas F. Barratt, Mohammed Z. Ali, Nathaniel J. Szewczyk

Functional phosphatome requirement for protein homeostasis, networked mitochondria, and sarcomere structure in C. elegans muscleBackground
Skeletal muscle is central to locomotion and metabolic homeostasis. The laboratory worm Caenorhabditis elegans has been developed into a genomic model for assessing the genes and signals that regulate muscle development and protein degradation. Past work has identified a receptor tyrosine kinase signalling network that combinatorially controls autophagy, nerve signal to muscle to oppose proteasome-based degradation, and extracellular matrix-based signals that control calpain and caspase activation. The last two discoveries were enabled by following up results from a functional genomic screen of known regulators of muscle. Recently, a screen of the kinome requirement for muscle homeostasis identified roughly 40% of kinases as required for C. elegans muscle health; 80 have identified human orthologues and 53 are known to be expressed in skeletal muscle. To complement this kinome screen, here, we screen most of the phosphatases in C. elegans.
Methods
RNA interference was used to knockdown phosphatase-encoding genes. Knockdown was first conducted during development with positive results also knocked down only in fully developed adult muscle. Protein homeostasis, mitochondrial structure, and sarcomere structure were assessed using transgenic reporter proteins. Genes identified as being required to prevent protein degradation were also knocked down in conditions that blocked proteasome or autophagic degradation. Genes identified as being required to prevent autophagic degradation were also assessed for autophagic vesicle accumulation using another transgenic reporter. Lastly, bioinformatics were used to look for overlap between kinases and phosphatases required for muscle homeostasis, and the prediction that one phosphatase was required to prevent mitogen-activated protein kinase activation was assessed by western blot.
Results
A little over half of all phosphatases are each required to prevent abnormal development or maintenance of muscle. Eighty-six of these phosphatases have known human orthologues, 57 of which are known to be expressed in human skeletal muscle. Of the phosphatases required to prevent abnormal muscle protein degradation, roughly half are required to prevent increased autophagy.
Conclusions
A significant portion of both the kinome and phosphatome are required for establishing and maintaining C. elegans muscle health. Autophagy appears to be the most commonly triggered form of protein degradation in response to disruption of phosphorylation-based signalling. The results from these screens provide measurable phenotypes for analysing the combined contribution of kinases and phosphatases in a multi-cellular organism and suggest new potential regulators of human skeletal muscle for further analysis.

 

Lehmann, S., Bass, J. J., Barratt, T. F., Ali, M. Z., and Szewczyk, N. J. (2017) Functional phosphatome requirement for protein homeostasis, networked mitochondria, and sarcomere structure in C. elegans muscle. Journal of Cachexia, Sarcopenia and Muscle, 8: 660–672. doi: 10.1002/jcsm.12196.

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Number 5 / October 2017

 

     Page 675–680

Stephan von Haehling, Nicole Ebner, Stefan D. Anker

Oodles of opportunities: the Journal of Cachexia, Sarcopenia and Muscle in 2017no abstract

 

von Haehling, S., Ebner, N., and Anker, S. D. (2017) Oodles of opportunities: the Journal of Cachexia, Sarcopenia and Muscle in 2017. Journal of Cachexia, Sarcopenia and Muscle, 8: 675–680. doi: 10.1002/jcsm.12247.

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     Page 681–685

Maggie C. Walter, Peter Reilich

Recent developments in Duchenne muscular dystrophy: facts and numbersno abstract

 

Walter, M. C., and Reilich, P. (2017) Recent developments in Duchenne muscular dystrophy: facts and numbers. Journal of Cachexia, Sarcopenia and Muscle, 8: 681–685. doi: 10.1002/jcsm.12245.

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     Page 686–701

Pablo Molina, Juan J. Carrero, Jordi Bover, Philippe Chauveau, Sandro Mazzaferro, Pablo Ureña Torres and for the European Renal Nutrition (ERN) and Chronic Kidney Disease-Mineral and Bone Disorder (CKD-MBD) Working Groups of the European Renal Association–European Dialysis Transplant Association (ERA-EDTA)

Vitamin D, a modulator of musculoskeletal health in chronic kidney diseaseThe spectrum of activity of vitamin D goes beyond calcium and bone homeostasis, and growing evidence suggests that vitamin D contributes to maintain musculoskeletal health in healthy subjects as well as in patients with chronic kidney disease (CKD), who display the combination of bone metabolism disorder, muscle wasting, and weakness. Here, we review how vitamin D represents a pathway in which bone and muscle may interact. In vitro studies have confirmed that the vitamin D receptor is present on muscle, describing the mechanisms whereby vitamin D directly affects skeletal muscle. These include genomic and non-genomic (rapid) effects, regulating cellular differentiation and proliferation. Observational studies have shown that circulating 25-hydroxyvitamin D levels correlate with the clinical symptoms and muscle morphological changes observed in CKD patients. Vitamin D deficiency has been linked to low bone formation rate and bone mineral density, with an increased risk of skeletal fractures. The impact of low vitamin D status on skeletal muscle may also affect muscle metabolic pathways, including its sensitivity to insulin. Although some interventional studies have shown that vitamin D may improve physical performance and protect against the development of histological and radiological signs of hyperparathyroidism, evidence is still insufficient to draw definitive conclusions.

 

Molina, P., Carrero, J. J., Bover, J., Chauveau, P., Mazzaferro, S., Torres, P. U., and for the European Renal Nutrition (ERN) and Chronic Kidney Disease-Mineral and Bone Disorder (CKD-MBD) Working Groups of the European Renal Association–European Dialysis Transplant Association (ERA-EDTA) (2017) Vitamin D, a modulator of musculoskeletal health in chronic kidney disease. Journal of Cachexia, Sarcopenia and Muscle, 8: 686–701. doi: 10.1002/jcsm.12218.

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     Page 702–712

Willemke Nijholt, Aldo Scafoglieri, Harriët Jager-Wittenaar, Johannes S.M. Hobbelen, Cees P. van der Schans

The reliability and validity of ultrasound to quantify muscles in older adults: a systematic reviewThis review evaluates the reliability and validity of ultrasound to quantify muscles in older adults. The databases PubMed, Cochrane, and Cumulative Index to Nursing and Allied Health Literature were systematically searched for studies. In 17 studies, the reliability (n = 13) and validity (n = 8) of ultrasound to quantify muscles in community-dwelling older adults (=60 years) or a clinical population were evaluated. Four out of 13 reliability studies investigated both intra-rater and inter-rater reliability. Intraclass correlation coefficient (ICC) scores for reliability ranged from -0.26 to 1.00. The highest ICC scores were found for the vastus lateralis, rectus femoris, upper arm anterior, and the trunk (ICC = 0.72 to 1.000). All included validity studies found ICC scores ranging from 0.92 to 0.999. Two studies describing the validity of ultrasound to predict lean body mass showed good validity as compared with dual-energy X-ray absorptiometry (r2 = 0.92 to 0.96). This systematic review shows that ultrasound is a reliable and valid tool for the assessment of muscle size in older adults. More high-quality research is required to confirm these findings in both clinical and healthy populations. Furthermore, ultrasound assessment of small muscles needs further evaluation. Ultrasound to predict lean body mass is feasible; however, future research is required to validate prediction equations in older adults with varying function and health.

 

Nijholt, W., Scafoglieri, A., Jager-Wittenaar, H., Hobbelen, J. S. M., and van der Schans, C. P. (2017) The reliability and validity of ultrasound to quantify muscles in older adults: a systematic review. Journal of Cachexia, Sarcopenia and Muscle, 8: 702–712. doi: 10.1002/jcsm.12210.

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     Page 713–726

Michael T. Paris, Benoit Lafleur, Joel A. Dubin, Marina Mourtzakis

Development of a bedside viable ultrasound protocol to quantify appendicular lean tissue massBackground
Ultrasound is a non-invasive and readily available tool that can be prospectively applied at the bedside to assess muscle mass in clinical settings. The four-site protocol, which images two anatomical sites on each quadriceps, may be a viable bedside method, but its ability to predict musculature has not been compared against whole-body reference methods. Our primary objectives were to (i) compare the four-site protocol's ability to predict appendicular lean tissue mass from dual-energy X-ray absorptiometry; (ii) optimize the predictability of the four-site protocol with additional anatomical muscle thicknesses and easily obtained covariates; and (iii) assess the ability of the optimized protocol to identify individuals with low lean tissue mass.
Methods
This observational cross-sectional study recruited 96 university and community dwelling adults. Participants underwent ultrasound scans for assessment of muscle thickness and whole-body dual-energy X-ray absorptiometry scans for assessment of appendicular lean tissue. Ultrasound protocols included (i) the nine-site protocol, which images nine anterior and posterior muscle groups in supine and prone positions, and (ii) the four-site protocol, which images two anterior sites on each quadriceps muscle group in a supine position.
Results
The four-site protocol was strongly associated (R2 = 0.72) with appendicular lean tissue mass, but Bland–Altman analysis displayed wide limits of agreement (-5.67, 5.67 kg). Incorporating the anterior upper arm muscle thickness, and covariates age and sex, alongside the four-site protocol, improved the association (R2 = 0.91) with appendicular lean tissue and displayed narrower limits of agreement (-3.18, 3.18 kg). The optimized protocol demonstrated a strong ability to identify low lean tissue mass (area under the curve = 0.89).
Conclusions
The four-site protocol can be improved with the addition of the anterior upper arm muscle thickness, sex, and age when predicting appendicular lean tissue mass. This optimized protocol can accurately identify low lean tissue mass, while still being easily applied at the bedside.

 

Paris, M. T., Lafleur, B., Dubin, J. A., and Mourtzakis, M. (2017) Development of a bedside viable ultrasound protocol to quantify appendicular lean tissue mass. Journal of Cachexia, Sarcopenia and Muscle, 8: 713–726. doi: 10.1002/jcsm.12213.

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     Page 727–734

Daniel S. Rooks, Didier Laurent, Jens Praestgaard, Scott Rasmussen, Michael Bartlett, László B. Tankó

Effect of bimagrumab on thigh muscle volume and composition in men with casting-induced atrophyBackground
Patients experiencing disuse atrophy report acute loss of skeletal muscle mass which subsequently leads to loss of strength and physical capacity. In such patients, especially the elderly, complete recovery remains a challenge even with improved nutrition and resistance exercise. This study aimed to explore the clinical potential of bimagrumab, a human monoclonal antibody targeting the activin type II receptor, for the recovery of skeletal muscle volume from disuse atrophy using an experimental model of lower extremity immobilization.
Methods
In this double-blind, placebo-controlled trial, healthy young men (n = 24; mean age, 24.1 years) were placed in a full-length cast of one of the lower extremities for 2 weeks to induce disuse atrophy. After cast removal, subjects were randomized to receive a single intravenous (i.v.) dose of either bimagrumab 30 mg/kg (n = 15) or placebo (n = 9) and were followed for 12 weeks. Changes in thigh muscle volume (TMV) and inter-muscular adipose tissue (IMAT) and subcutaneous adipose tissue (SCAT) of the thigh, maximum voluntary knee extension strength, and safety were assessed throughout the 12 week study.
Results
Casting resulted in an average TMV loss of -4.8% and comparable increases in IMAT and SCAT volumes. Bimagrumab 30 mg/kg i.v. resulted in a rapid increase in TMV at 2 weeks following cast removal and a +5.1% increase above pre-cast levels at 12 weeks. In comparison, TMV returned to pre-cast level at 12 weeks (-0.1%) in the placebo group. The increased adiposity of the casted leg was sustained in the placebo group and decreased substantially in the bimagrumab group at Week 12 (IMAT: -6.6%, SCAT: -3.5%). Knee extension strength decreased by ~25% in the casted leg for all subjects and returned to pre-cast levels within 6 weeks after cast removal in both treatment arms. Bimagrumab was well tolerated with no serious or severe adverse events reported during the study.

 

Rooks, D. S., Laurent, D., Praestgaard, J., Rasmussen, S., Bartlett, M., and Tankó, Ló. B. (2017) Effect of bimagrumab on thigh muscle volume and composition in men with casting-induced atrophy. Journal of Cachexia, Sarcopenia and Muscle, 8: 727–734. doi: 10.1002/jcsm.12205.

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     Page 735–747

Yuki Enoki, Hiroshi Watanabe, Riho Arake, Rui Fujimura, Kana Ishiodori, Tadashi Imafuku, Kento Nishida, Ryusei Sugimoto, Saori Nagao, Shigeyuki Miyamura, Yu Ishima, Motoko Tanaka, Kazutaka Matsushita, Hirotaka Komaba, Masafumi Fukagawa, Masaki Otagiri, Toru Maruyama

Potential therapeutic interventions for chronic kidney disease-associated sarcopenia via indoxyl sulfate-induced mitochondrial dysfunctionBackground
Chronic kidney disease (CKD) patients experience skeletal muscle wasting and decreased exercise endurance. Our previous study demonstrated that indoxyl sulfate (IS), a uremic toxin, accelerates skeletal muscle atrophy. The purpose of this study was to examine the issue of whether IS causes mitochondria dysfunction and IS-targeted intervention using AST-120, which inhibits IS accumulation, or mitochondria-targeted intervention using L-carnitine or teneligliptin, a dipeptidyl peptidase-4 inhibitor which retains mitochondria function and alleviates skeletal muscle atrophy and muscle endurance in chronic kidney disease mice.
Methods
The in vitro effect of IS on mitochondrial status was evaluated using mouse myofibroblast cells (C2C12 cell). The mice were divided into sham or 5/6-nephrectomized (CKD) mice group. Chronic kidney disease mice were also randomly assigned to non-treatment group and AST-120, L-carnitine, or teneligliptin treatment groups.
Results
In C2C12 cells, IS induced mitochondrial dysfunction by decreasing the expression of PGC-1a and inducing autophagy in addition to decreasing mitochondrial membrane potential. Co-incubation with an anti-oxidant, ascorbic acid, L-carnitine, or teneligliptine restored the values to their original state. In CKD mice, the body and skeletal muscle weights were decreased compared with sham mice. Compared with sham mice, the expression of interleukin-6 and atrophy-related factors such as myostatin and atrogin-1 was increased in the skeletal muscle of CKD mice, whereas muscular Akt phosphorylation was decreased. In addition, a reduced exercise capacity was observed for the CKD mice, which was accompanied by a decreased expression of muscular PCG-1a and increased muscular autophagy, as reflected by decreased mitochondria-rich type I fibres. An AST-120 treatment significantly restored these changes including skeletal muscle weight observed in CKD mice to the sham levels accompanied by a reduction in IS levels. An L-carnitine or teneligliptin treatment also restored them to the sham levels without changing IS level.
Conclusions
Our results indicate that IS induces mitochondrial dysfunction in skeletal muscle cells and provides a potential therapeutic strategy such as IS-targeted and mitochondria-targeted interventions for treating CKD-induced muscle atrophy and decreased exercise endurance.

 

Enoki, Y., Watanabe, H., Arake, R., Fujimura, R., Ishiodori, K., Imafuku, T., Nishida, K., Sugimoto, R., Nagao, S., Miyamura, S., Ishima, Y., Tanaka, M., Matsushita, K., Komaba, H., Fukagawa, M., Otagiri, M., and Maruyama, T. (2017) Potential therapeutic interventions for chronic kidney disease-associated sarcopenia via indoxyl sulfate-induced mitochondrial dysfunction. Journal of Cachexia, Sarcopenia and Muscle, 8: 735–747. doi: 10.1002/jcsm.12202.

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     Page 748–758

Coby van de Bool, Erica P.A. Rutten, Ardy van Helvoort, Frits M.E. Franssen, Emiel F.M. Wouters, Annemie M.W.J. Schols

A randomized clinical trial investigating the efficacy of targeted nutrition as adjunct to exercise training in COPDBackground
Evidence regarding the efficacy of nutritional supplementation to enhance exercise training responses in COPD patients with low muscle mass is limited.
The objective was to study if nutritional supplementation targeting muscle derangements enhances outcome of exercise training in COPD patients with low muscle mass.
Methods
Eighty-one COPD patients with low muscle mass, admitted to out-patient pulmonary rehabilitation, randomly received oral nutritional supplementation, enriched with leucine, vitamin D, and omega-3 fatty acids (NUTRITION) or PLACEBO as adjunct to 4 months supervised high intensity exercise training.
Results
The study population (51% males, aged 43–80) showed moderate airflow limitation, low diffusion capacity, normal protein intake, low plasma vitamin D, and docosahexaenoic acid. Intention-to-treat analysis revealed significant differences after 4 months favouring NUTRITION for body mass (mean difference ± SEM) (+1.5 ± 0.6 kg, P = 0.01), plasma vitamin D (+24%, P = 0.004), eicosapentaenoic acid (+91%,P < 0.001), docosahexaenoic acid (+31%, P < 0.001), and steps/day (+24%, P = 0.048). After 4 months, both groups improved skeletal muscle mass (+0.4 ± 0.1 kg, P < 0.001), quadriceps muscle strength (+12.3 ± 2.3 Nm,P < 0.001), and cycle endurance time (+191.4 ± 34.3 s, P < 0.001). Inspiratory muscle strength only improved in NUTRITION (+0.5 ± 0.1 kPa, P = 0.001) and steps/day declined in PLACEBO (-18%,P = 0.005).
Conclusions
High intensity exercise training is effective in improving lower limb muscle strength and exercise performance in COPD patients with low muscle mass and moderate airflow obstruction. Specific nutritional supplementation had additional effects on nutritional status, inspiratory muscle strength, and physical activity compared with placebo.

 

van de Bool, C., Rutten, E. P. A., van Helvoort, A., Franssen, F. M. E., Wouters, E. F. M., and Schols, A. M. W. J. (2017) A randomized clinical trial investigating the efficacy of targeted nutrition as adjunct to exercise training in COPD. Journal of Cachexia, Sarcopenia and Muscle, 8: 748–758. doi: 10.1002/jcsm.12219.

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     Page 702–712

Asta Bye, Bjørg Sjøblom, Tore Wentzel-Larsen, Bjørn H. Grønberg, Vickie E. Baracos, Marianne J. Hjermstad, Nina Aass, Roy M. Bremnes, Øystein Fløtten, Marit Jordhøy

Muscle mass and association to quality of life in non-small cell lung cancer patientsBackground
Cancer wasting is characterized by muscle loss and may contribute to fatigue and poor quality of life (QoL). Our aim was to investigate associations between skeletal muscle index (SMI) and skeletal muscle radiodensity (SMD) and selected QoL outcomes in advanced non-small cell lung cancer (NSCLC) at diagnosis.
Methods
Baseline data from patients with stage IIIB/IV NSCLC and performance status 0–2 enrolled in three randomized trials of first-line chemotherapy (n = 1305) were analysed. Associations between SMI (cm2/m2) and SMD (Hounsfield units) based on computed tomography-images at the third lumbar level and self-reported physical function (PF), role function (RF), global QoL, fatigue, and dyspnoea were investigated by linear regression using flexible non-linear modelling.
Results
Complete data were available for 734 patients, mean age 65 years. Mean SMI was 47.7 cm2/m2 in men (n = 420) and 39.6 cm2/m2 in women (n = 314). Low SMI values were non-linearly associated with low PF and RF (men P = 0.016/0.020, women P = 0.004/0.012) and with low global QoL (P = 0.001) in men. Low SMI was significantly associated with high fatigue (P = 0.002) and more pain (P = 0.015), in both genders, but not with dyspnoea. All regression analyses showed poorer physical outcomes below an SMI breakpoint of about 42–45 cm2/m2 for men and 37–40 cm2/m2 for women. In both genders, poor PF and more dyspnoea were significantly associated with low SMD.
Conclusions
Low muscle mass in NSCLC negatively affects the patients' PF, RF, and global QoL, possibly more so in men than in women. However, muscle mass must be below a threshold value before this effect can be detected.

 

Bye, A., Sjøblom, B., Wentzel-Larsen, T., Grønberg, B. H., Baracos, V. E., Hjermstad, M. J., Aass, N., Bremnes, R. M., Fløtten, Ø., and Jordhøy, M. (2017) Muscle mass and association to quality of life in non-small cell lung cancer patients. Journal of Cachexia, Sarcopenia and Muscle, 8: 759–767. doi: 10.1002/jcsm.12206.2206.

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     Page 768–777

Audrey Loumaye, Marie de Barsy, Maxime Nachit, Pascale Lause, Aline van Maanen, Pierre Trefois, Damien Gruson, Jean-Paul Thissen

Circulating Activin A predicts survival in cancer patientsBackground
Several experimental evidences pinpoint the possible role of Activin A (ActA) as a driver of cancer cachexia. Supporting this hypothesis, we showed recently that human cancer cachexia is associated with high ActA levels. Moreover, ActA levels were correlated with body weight loss and skeletal muscle density, two prognostic factors in cancer patients. Our goal was therefore to investigate the value of ActA to predict survival in cancer patients.
Methods
Patients with colorectal or lung cancer were prospectively enrolled at the time of diagnosis or relapse between January 2012 and March 2014. At baseline, patients had clinical, nutritional, and functional assessment. Body composition and skeletal muscle density were measured by CT scan, and plasma ActA concentrations were determined. Overall survival (OS) was analysed since inclusion to 24 months later.
Results
Survival data were available for 149 patients out of 152. Patients with high ActA (=408 pg/mL) had lower OS than those with low levels, regardless the type of cancer (OS in colorectal cancer, 50% vs. 79%, P < 0.05; and in lung cancer, 27% vs. 67%, P = 0.001). The multivariable analysis confirmed the prognostic value of ActA independently of tumour stage or inflammatory markers, particularly in lung cancer. Low muscularity was also an independent prognostic factor.
Conclusions
Our study demonstrates that high ActA level is an independent prognosis factor of survival in cancer patients. More than a basic marker of the severity of the neoplastic disease or of the inflammatory process, ActA seems to influence survival by contributing to the development of cachexia and loss of skeletal muscle mass.

 

Loumaye, A., de Barsy, M., Nachit, M., Lause, P., van Maanen, A., Trefois, P., Gruson, D., and Thissen, J.-P. (2017) Circulating Activin A predicts survival in cancer patients. Journal of Cachexia, Sarcopenia and Muscle, 8: 768–777. doi: 10.1002/jcsm.12209.

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     Page 778–788

Tora S. Solheim, Barry J.A. Laird, Trude Rakel Balstad, Guro B . Stene,AstaBye, Neil Johns,Caroline H. Pettersen, Marie Fallon, Peter Fayers, Kenneth Fearon, Stein Kaasa

A randomized phase II feasibility trial of a multimodal intervention for the management of cachexia in lung and pancreatic cancerBackground
Cancer cachexia is a syndrome of weight loss (including muscle and fat), anorexia, and decreased physical function. It has been suggested that the optimal treatment for cachexia should be a multimodal intervention. The primary aim of this study was to examine the feasibility and safety of a multimodal intervention (n-3 polyunsaturated fatty acid nutritional supplements, exercise, and anti-inflammatory medication: celecoxib) for cancer cachexia in patients with incurable lung or pancreatic cancer, undergoing chemotherapy.
Methods
Patients receiving two cycles of standard chemotherapy were randomized to either the multimodal cachexia intervention or standard care. Primary outcome measures were feasibility assessed by recruitment, attrition, and compliance with intervention (>50% of components in >50% of patients). Key secondary outcomes were change in weight, muscle mass, physical activity, safety, and survival.
Results
Three hundred and ninety-nine were screened resulting in 46 patients recruited (11.5%). Twenty five patients were randomized to the treatment and 21 as controls. Forty-one completed the study (attrition rate 11%). Compliance to the individual components of the intervention was 76% for celecoxib, 60% for exercise, and 48% for nutritional supplements. As expected from the sample size, there was no statistically significant effect on physical activity or muscle mass. There were no intervention-related Serious Adverse Events and survival was similar between the groups.
Conclusions
A multimodal cachexia intervention is feasible and safe in patients with incurable lung or pancreatic cancer; however, compliance to nutritional supplements was suboptimal. A phase III study is now underway to assess fully the effect of the intervention.

 

Solheim, T. S., Laird, B. J. A., Balstad, T. R., Stene, G. B., Bye, A., Johns, N., Pettersen, C. H., Fallon, M., Fayers, P., Fearon, K., and Kaasa, S. (2017) A randomized phase II feasibility trial of a multimodal intervention for the management of cachexia in lung and pancreatic cancer. Journal of Cachexia, Sarcopenia and Muscle, 8: 778–788. doi: 10.1002/jcsm.12209.

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     Page 789–797

Ola Magne Vagnildhaug, David Blum, Andrew Wilcock, Peter Fayers, Florian Strasser, Vickie E. Baracos, Marianne J. Hjermstad, Stein Kaasa, Barry Laird, Tora S. Solheim and for the European Palliative Care Cancer Symptom study group

The applicability of a weight loss grading system in cancer cachexia: a longitudinal analysisBackground
A body mass index (BMI) adjusted weight loss grading system (WLGS) is related to survival in patients with cancer. The aim of this study was to examine the applicability of the WLGS by confirming its prognostic validity, evaluating its relationship to cachexia domains, and exploring its ability to predict cachexia progression.
Methods
An international, prospective observational study of patients with incurable cancer was conducted. For each patient, weight loss grade was scored 0–4. Weight loss grade 0 represents a high BMI with limited weight loss, progressing through to weight loss grade 4 representing low BMI and a high degree of weight loss. Survival analyses were used to confirm prognostic validity. Analyses of variance were used to evaluate the relationship between the WLGS and cachexia domains [anorexia, dietary intake, Karnofsky performance status (KPS), and physical and emotional functioning]. Cox regression was used to evaluate if the addition of cachexia domains to the WLGS improved prognostic accuracy. Predictive ability of cachexia progression was assessed by estimating proportion of patients progressing to a more advanced weight loss grade.
Results
One thousand four hundred six patients were analysed (median age 66 years; 50% female, 63% KPS = 70). The overall effect of the WLGS on survival was significant as expressed by change in -2 log likelihood (P < 0.001) and persisted after adjustment for age, sex, and cancer type and stage (P < 0.001). Median survival decreased across the weight loss grades ranging from 407 days (95% CI 312–502)—weight loss grade 0 to 119 days (95% CI 93–145)—weight loss grade 4. All cachexia domains significantly deteriorated with increasing weight loss grade, and deterioration was greatest for dietary intake, with a difference corresponding to 0.87 standard deviations between weight loss grades 0 and 4. The addition of KPS, anorexia, and physical and emotional functioning improved the prognostic accuracy of the WLGS. Likelihood of cachexia progression was greater in patients with weight loss grade 2 (39%) than that with weight loss grade 0 (19%) or 1 (22%).
Conclusions
The WLGS is related to survival, cachexia domains, and the likelihood of progression. Adding certain cachexia domains to the WLGS improves prognostic accuracy.

 

Vagnildhaug, O. M., Blum, D., Wilcock, A., Fayers, P., Strasser, F., Baracos, V. E., Hjermstad, M. J., Kaasa, S., Laird, B., Solheim, T. S., and for the European Palliative Care Cancer Symptom study group (2017) The applicability of a weight loss grading system in cancer cachexia: a longitudinal analysis. Journal of Cachexia, Sarcopenia and Muscle, 8: 789–797. doi: 10.1002/jcsm.12220.

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     Page 798–807

Vered Raz, Yotam Raz, Guillem Paniagua-Soriano, Jacomina Cornelia Roorda, Cyriel Olie, Muhammad Riaz, Bogdan I. Florea

Proteasomal activity-based probes mark protein homeostasis in musclesBackground
Protein homeostasis, primarily regulated by the ubiquitin–proteasome system is crucial for proper function of cells. In tissues of post-mitotic cells, the impaired ubiquitin–proteasome system is found in a wide range of neuromuscular disorders. Activity-based probes (ABPs) measure proteasomal proteolytic subunits and can be used to report protein homeostasis. Despite the crucial role of the proteasome in neuromuscular pathologies, ABPs were not employed in muscle cells and tissues, and measurement of proteasomal activity was carried out in vitro using low-throughput procedures.
Methods
We screened six ABPs for specific application in muscle cell culture using high throughput call-based imaging procedures. We then determined an in situ proteasomal activity in myofibers of muscle cryosections.
Results
We demonstrate that LWA300, a pan-reactive proteasomal probe, is most suitable to report proteasomal activity in muscle cells using cell-based bio-imaging. We found that proteasomal activity is two-fold and three-fold enhanced in fused muscle cell culture compared with non-fused cells. Moreover, we found that proteasomal activity can discriminate between muscles. Across muscles, a relative higher proteasomal activity was found in hybrid myofibers whereas fast-twitch myofibers displayed lower activity.
Conclusions
Our study demonstrates that proteasomal activity differ between muscles and between myofiber types. We suggest that ABPs can be used to report disease progression and treatment efficacy.

 

Raz, V., Raz, Y., Paniagua-Soriano, G., Roorda, J. C., Olie, C., Riaz, M., and Florea, B. I. (2017) Proteasomal activity-based probes mark protein homeostasis in muscles. Journal of Cachexia, Sarcopenia and Muscle, 8: 798–807. doi: 10.1002/jcsm.12211.

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     Page 808–823

Zherong Xu, Xin Feng, Juan Dong, Zhong-Min Wang, Jingyun Lee, Cristina Furdui, Daniel Clark Files, Kristen M. Beavers, Stephen Kritchevsky, Carolanne Milligan, Jian-Ping Jin, Osvaldo Delbono and Tan Zhang

Cardiac troponin T and fast skeletal muscle denervation in ageingBackground
Ageing skeletal muscle undergoes chronic denervation, and the neuromuscular junction (NMJ), the key structure that connects motor neuron nerves with muscle cells, shows increased defects with ageing. Previous studies in various species have shown that with ageing, type II fast-twitch skeletal muscle fibres show more atrophy and NMJ deterioration than type I slow-twitch fibres. However, how this process is regulated is largely unknown. A better understanding of the mechanisms regulating skeletal muscle fibre-type specific denervation at the NMJ could be critical to identifying novel treatments for sarcopenia. Cardiac troponin T (cTnT), the heart muscle-specific isoform of TnT, is a key component of the mechanisms of muscle contraction. It is expressed in skeletal muscle during early development, after acute sciatic nerve denervation, in various neuromuscular diseases and possibly in ageing muscle. Yet the subcellular localization and function of cTnT in skeletal muscle is largely unknown.
Methods
Studies were carried out on isolated skeletal muscles from mice, vervet monkeys, and humans. Immunoblotting, immunoprecipitation, and mass spectrometry were used to analyse protein expression, real-time reverse transcription polymerase chain reaction was used to measure gene expression, immunofluorescence staining was performed for subcellular distribution assay of proteins, and electromyographic recording was used to analyse neurotransmission at the NMJ.
Results
Levels of cTnT expression in skeletal muscle increased with ageing in mice. In addition, cTnT was highly enriched at the NMJ region—but mainly in the fast-twitch, not the slow-twitch, muscle of old mice. We further found that the protein kinase A (PKA) RIa subunit was largely removed from, while PKA RIIa and RIIß are enriched at, the NMJ—again, preferentially in fast-twitch but not slow-twitch muscle in old mice. Knocking down cTnT in fast skeletal muscle of old mice: (i) increased PKA RIa and reduced PKA RIIa at the NMJ; (ii) decreased the levels of gene expression of muscle denervation markers; and (iii) enhanced neurotransmission efficiency at NMJ.
Conclusions
Cardiac troponin T at the NMJ region contributes to NMJ functional decline with ageing mainly in the fast-twitch skeletal muscle through interfering with PKA signalling. This knowledge could inform useful targets for prevention and therapy of age-related decline in muscle function.

 

Xu, Z., Feng, X., Dong, J., Wang, Z.-M., Lee, J., Furdui, C., Files, D. C., Beavers, K. M., Kritchevsky, S., Milligan, C., Jin, J.-P., Delbono, O., and Zhang, T. (2017) Cardiac troponin T and fast skeletal muscle denervation in ageing. Journal of Cachexia, Sarcopenia and Muscle, 8: 808–823. doi: 10.1002/jcsm.12204.

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     Page 824–838

Katherine A. Michaelis, Xinxia Zhu, Kevin G. Burfeind, Stephanie M. Krasnow, Peter R. Levasseur, Terry K. Morgan, Daniel L. Marks

Establishment and characterization of a novel murine model of pancreatic cancer cachexiaBackground
Cachexia is a complex metabolic and behavioural syndrome lacking effective therapies. Pancreatic ductal adenocarcinoma (PDAC) is one of the most important conditions associated with cachexia, with >80% of PDAC patients suffering from the condition. To establish the cardinal features of a murine model of PDAC-associated cachexia, we characterized the effects of implanting a pancreatic tumour cell line from a syngeneic C57BL/6 KRASG12D P53R172H Pdx-Cre+/+ (KPC) mouse.
Methods
Male and female C57BL/6 mice were inoculated subcutaneously, intraperitoneally, or orthotopically with KPC tumour cells. We performed rigorous phenotypic, metabolic, and behavioural analysis of animals over the course of tumour development.
Results
All routes of administration produced rapidly growing tumours histologically consistent with moderate to poorly differentiated PDAC. The phenotype of this model was dependent on route of administration, with orthotopic and intraperitoneal implantation inducing more severe cachexia than subcutaneous implantation. KPC tumour growth decreased food intake, decreased adiposity and lean body mass, and decreased locomotor activity. Muscle catabolism was observed in both skeletal and cardiac muscles, but the dominant catabolic pathway differed between these tissues. The wasting syndrome in this model was accompanied by hypothalamic inflammation, progressively decreasing brown and white adipose tissue uncoupling protein 1 (Ucp1) expression, and increased peripheral inflammation. Haematological and endocrine abnormalities included neutrophil-dominant leukocytosis and anaemia, and decreased serum testosterone.
Conclusions
Syngeneic KPC allografts are a robust model for studying cachexia, which recapitulate key features of the PDAC disease process and induce a wide array of cachexia manifestations. This model is therefore ideally suited for future studies exploring the physiological systems involved in cachexia and for preclinical studies of novel therapies.

 

Michaelis, K. A., Zhu, X., Burfeind, K. G., Krasnow, S. M., Levasseur, P. R., Morgan, T. K., and Marks, D. L. (2017) Establishment and characterization of a novel murine model of pancreatic cancer cachexia. Journal of Cachexia, Sarcopenia and Muscle, 8: 824838. doi: 10.1002/jcsm.12225.

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     Page 839–850

Yong-Soo Lee, Ja-Yeon Kim, Kyung-Soo Oh, Seok Won Chung

Fatty acid-binding protein 4 regulates fatty infiltration after rotator cuff tear by hypoxia-inducible factor 1 in miceBackground
Fatty infiltration in skeletal muscle is directly linked to loss of muscle strength and is associated with various adverse physical outcomes such as muscle atrophy, inflammation, insulin resistance, mobility impairments, and even mortality in the elderly. Aging, mechanical unloading, muscle injury, and hormonal imbalance are main causes of muscle fat accumulation, and the fat cells are derived from muscle stem cells via adipogenic differentiation. However, the pathogenesis and molecular mechanisms of fatty infiltration in muscles are still not fully defined. Fatty acid-binding protein 4 (FABP4) is a carrier protein for fatty acids and is involved in fatty acid uptake, transport, and lipid metabolism. Rotator cuff tear (RCT) usually occurs in the elderly and is closely related with fatty infiltration in injured muscle. To investigate potential mechanisms for fatty infiltration other than adipogenic differentiation of muscle stem cells, we examined the role of FABP4 in muscle fatty infiltration in an RCT mouse model.
Methods
In the RCT model, we evaluated the expression of FABP4 by qRT-PCR, western blotting, and immunohistochemical analyses. Histological changes such as inflammation and fat accumulation in the injured muscles were examined immunohistochemically. To evaluate whether hypoxia induces FABP4 expression, the levels of FABP4 mRNA and protein in C3H10T1/2 cells after hypoxia were examined. Using a transient transfection assay in 293T cells, we assessed the promoter activity of FABP4 by hypoxia-inducible factors (HIFs). Additionally, we evaluated the reduction in FABP4 expression and fat accumulation using specific inhibitors for HIF1 and FABP4, respectively.
Results
FABP4 expression was significantly increased after RCT in mice, and its expression was localized in the intramuscular fatty region. Rotator cuff tear-induced FABP4 expression was up-regulated by hypoxia. HIF1a, which is activated by hypoxia, augmented the promoter activity of FABP4, together with HIF1ß. Hypoxia-induced FABP4 expression was significantly decreased by HIF1 inhibitor treatment. Furthermore, in RCT model mice, fat accumulation was remarkably reduced by FABP4 inhibitor treatment.
Conclusions
This study shows that RCT induces FABP4 expression, leading to fat accumulation in injured muscle. FABP4 transcription is regulated by the direct binding of HIF1 to the FABP4 promoter in the hypoxic condition induced by RCT. Fat accumulation in injured muscle was reduced by the inhibition of FABP4. Ultimately, in the RCT model, we identified a novel mechanism for fatty infiltration by FABP4, which differs from adipogenic differentiation of muscle stem cells, and we found that fatty infiltration might be regulated by inhibition of HIF1 or FABP4.

 

Lee, Y.-S., Kim, J.-Y., Oh, K.-S., and Chung, S. W. (2017) Fatty acid-binding protein 4 regulates fatty infiltration after rotator cuff tear by hypoxia-inducible factor 1 in mice. Journal of Cachexia, Sarcopenia and Muscle, 8: 839–850. doi: 10.1002/jcsm.12203.

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     Page 851–852

Junichi Ishida, Masakazu Saitoh, Jochen Springer

Is cardiac wasting accompanied by skeletal muscle loss in breast cancer patients receiving anticancer treatment?no abstract

 

Ishida, J., Saitoh, M., and Springer, J. (2017) Is cardiac wasting accompanied by skeletal muscle loss in breast cancer patients receiving anticancer treatment?. Journal of Cachexia, Sarcopenia and Muscle, 8: 851–852. doi: 10.1002/jcsm.12229.

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     Page 853–854

Masakazu Saitoh, Junichi Ishida, Jochen Springer

Considering technique of assessment and method for normalizing skeletal muscle massno abstract

 

Saitoh, M., Ishida, J., and Springer, J. (2017) Considering technique of assessment and method for normalizing skeletal muscle mass. Journal of Cachexia, Sarcopenia and Muscle, 8: 853–854. doi: 10.1002/jcsm.12230.

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Number 6 / December 2017

 

     Page 857–863

John E. Morley, Stefan D. Anker

Myopenia and precision (P4) medicinePrecision (P4) medicine represents a new medical paradigm that focuses on Personalized, Predictive, Preventive and Participatory approaches. The P4 paradigm is particularly appropriate for moving the care of persons with myopenia forward. Muscular dystrophies are clearly a set of genetically different diseases where genomics are the basis of diagnosis, and genetic modulation via DNA, oligonucleotides and clustered regularly interspaced short palendronic repeats hold great potential for a cure. The utility of personalized genomics for sarcopenia coupled with utilizing a predictive approach for the diagnosis with early preventive strategies is a key to improving sarcopenic outcomes. The importance of understanding different levels of patient enthusiasm and different responses to exercise should guide the participatory phase of sarcopenic treatment. In the case of cachexia, understanding the effects of the different therapies now available through the P4 approach on muscle wasting is a key to management strategies.

 

Morley, J. E., and Anker, S. D. (2017) Myopenia and precision (P4) medicine. Journal of Cachexia, Sarcopenia and Muscle, 8: 954–973 doi: 10.1002/jcsm.12231.

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     Page 853–854

Srinivasan Dasarathy

Myostatin and beyond in cirrhosis: all roads lead to sarcopeniano abstract

 

Dasarathy, S. (2017) Myostatin and beyond in cirrhosis: all roads lead to sarcopenia. Journal of Cachexia, Sarcopenia and Muscle, 8: 853–854. doi: 10.1002/jcsm.12262.

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     Page 870–880

Stephan von Haehling

Casting the net broader to confirm our imaginations: the long road to treating wasting disordersWasting embraces muscle and tissue wasting in sarcopenia and cachexia. This article describes recent advances in the field published in the Journal of Cachexia, Sarcopenia and Muscle concerning diagnostic tools, biomarker development, pathophysiology, and treatment. Studies discussed herein embrace those on sarcopenia and cachexia in heart failure, chronic obstructive pulmonary disease, and cancer including also animal models.

 

von Haehling, S. (2017) Casting the net broader to confirm our imaginations: the long road to treating wasting disorders. Journal of Cachexia, Sarcopenia and Muscle, 8: 870–880. doi: 10.1002/jcsm.12256.

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     Page 881–906

Giorgos K. Sakellariou, Adam P. Lightfoot, Kate E. Earl, Martin Stofanko, Brian McDonagh

Redox homeostasis and age-related deficits in neuromuscular integrity and functionSkeletal muscle is a major site of metabolic activity and is the most abundant tissue in the human body. Age-related muscle atrophy (sarcopenia) and weakness, characterized by progressive loss of lean muscle mass and function, is a major contributor to morbidity and has a profound effect on the quality of life of older people. With a continuously growing older population (estimated 2 billion of people aged >60 by 2050), demand for medical and social care due to functional deficits, associated with neuromuscular ageing, will inevitably increase. Despite the importance of this ‘epidemic’ problem, the primary biochemical and molecular mechanisms underlying age-related deficits in neuromuscular integrity and function have not been fully determined. Skeletal muscle generates reactive oxygen and nitrogen species (RONS) from a variety of subcellular sources, and age-associated oxidative damage has been suggested to be a major factor contributing to the initiation and progression of muscle atrophy inherent with ageing. RONS can modulate a variety of intracellular signal transduction processes, and disruption of these events over time due to altered redox control has been proposed as an underlying mechanism of ageing. The role of oxidants in ageing has been extensively examined in different model organisms that have undergone genetic manipulations with inconsistent findings. Transgenic and knockout rodent studies have provided insight into the function of RONS regulatory systems in neuromuscular ageing. This review summarizes almost 30 years of research in the field of redox homeostasis and muscle ageing, providing a detailed discussion of the experimental approaches that have been undertaken in murine models to examine the role of redox regulation in age-related muscle atrophy and weakness.

 

Sakellariou, G. K., Lightfoot, A. P., Earl, K. E., Stofanko, M., and McDonagh, B. (2017) Redox homeostasis and age-related deficits in neuromuscular integrity and function. Journal of Cachexia, Sarcopenia and Muscle, 8: 881–906 doi: 10.1002/jcsm.12223.

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     Page 907–914

Anna Maria Martone, Lara Bianchi, Pasquale Abete, Giuseppe Bellelli, Mario Bo, Antonio Cherubini, Francesco Corica, Mauro Di Bari, Marcello Maggio, Giovanna Maria Manca, Emanuele Marzetti, Maria Rosaria Rizzo, Andrea Rossi, Stefano Volpato, Francesco Landi the GLISTEN Group Investigators

The incidence of sarcopenia among hospitalized older patients: results from the Glisten studyBackground
New evidence is emerging on the importance of lean body mass during periods of illness and recovery. The preservation of lean body mass during such periods of intense stress impacts both patient and treatment outcomes. However, data concerning the incidence of sarcopenia among older people during hospitalization are scarce. The objective of this study was to evaluate the development of sarcopenia in a sample of hospitalized older subjects.
Methods
We used data of 394 participants from the multicentre Italian Study conducted by the Gruppo Lavoro Italiano Sarcopenia—Trattamento e Nutrizione (GLISTEN) in 12 Acute Care Wards (Internal Medicine and Geriatrics) of University Hospitals across Italy. This study was designed to determine the prevalence of sarcopenia at hospital admission and the change in muscle mass and strength during hospitalization. Sarcopenia was defined as low skeletal mass index (kg/m2) along with either low handgrip strength or slow walking speed [European Working Groups on Sarcopenia in Older People (EWGSOP) criteria]. Estimation of skeletal muscle mass was performed by bioelectrical impedance analysis (BIA).
Results
The mean age of the 394 enrolled patients (including 211 females who accounted for 53% of the sample) was 79.6 ± 6.4 years. Among those without sarcopenia at hospital admission, 14.7% of the study sample met the EWGSOP sarcopenia diagnostic criteria at discharge. The incidence of sarcopenia during hospitalization was significantly associated with the number of days spent in bed but was not correlated with the total length of hospital stay. In particular, patients who developed sarcopenia spent an average of 5.1 days in bed compared with 3.2 days for those with no sarcopenia at discharge (P = 0.02). Patients with sarcopenia showed a significantly lower body mass index compared with non-sarcopenic peers (25.0 ± 3.8 kg/m2 vs. 27.6 ± 4.9 kg/m2, respectively; P < 0.001). Similarly, the skeletal mass index at admission was significantly lower among patients who developed sarcopenia during hospital stay.
Conclusions
Incident sarcopenia during hospital stay is relatively common and is associated with nutritional status and the number of days of bed rest.

 

Martone, A. M., Bianchi, L., Abete, P., Bellelli, G., Bo, M., Cherubini, A., Corica, F., Di Bari, M., Maggio, M., Manca, G. M., Marzetti, E., Rizzo, M. R., Rossi, A., Volpato, S., and Landi, F. (2017) The incidence of sarcopenia among hospitalized older patients: results from the Glisten study. Journal of Cachexia, Sarcopenia and Muscle, 8: 907–914 doi: 10.1002/jcsm.12224.

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     Page 915–925

Hiroki Nishikawa, Hirayuki Enomoto, Akio Ishii, Yoshinori Iwata, Yuho Miyamoto, Noriko Ishii, Yukihisa Yuri, Kunihiro Hasegawa, Chikage Nakano, Takashi Nishimura, Kazunori Yoh, Nobuhiro Aizawa, Yoshiyuki Sakai, Naoto Ikeda, Tomoyuki Takashima, Ryo Takata, Hiroko Iijima, Shuhei Nishiguchi

Elevated serum myostatin level is associated with worse survival in patients with liver cirrhosisBackground
We aimed to elucidate the relationship between serum myostatin levels and other markers including skeletal muscle mass and to investigate the influence of serum myostatin levels on survival for patients with liver cirrhosis (LC).
Methods
A total of 198 LC subjects were analysed in this study. Myostatin levels were measured using stored sera. We retrospectively investigated the relationship between myostatin level and other markers, and the influence of myostatin level on overall survival (OS). Assessment of skeletal muscle mass was performed using the psoas muscle index (PMI) on computed tomography images at baseline. PMI indicates the sum of bilateral psoas muscle mass calculated by hand tracing at the lumber three level on computed tomography images divided by height squared (cm2/m2). The study cohort was divided into two groups based on the median myostatin value in each gender.
Results
Our study cohort included 108 male and 90 female patients with a median age of 67.5 years. The median (range) myostatin level for male patients was 3419.6 pg/mL (578.4–12897.7 pg/mL), whereas that for female patients was 2662.4 pg/mL (710.4–8782.0 pg/mL) (P = 0.0024). Median (range) serum myostatin level for Child–Pugh A patients (n = 123) was 2726.0 pg/mL (578.4–12667.2 pg/mL), whereas that for Child–Pugh B or C patients (n = 75) was 3615.2 pg/mL (663.3–12897.7 pg/mL) (P = 0.0011). For the entire cohort, the 1-, 3-, 5-, and 7-year cumulative OS rates were 93.94%, 72.71%, 50.37%, and 38.47%, respectively, in the high-myostatin group and 96.97%, 83.27%, 73.60%, and 69.95%, respectively, in the low-myostatin group (P = 0.0001). After excluding hepatocellular carcinoma patients (at baseline) from our analysis (n = 158), the 1-, 3-, 5-, and 7-year cumulative OS rates were 96.0%, 77.93%, 52.97%, and 39.08%, respectively, in the high-myostatin group and 96.39%, 87.58%, 77.63%, and 73.24%, respectively, in the low-myostatin group (P = 0.0005). Higher age (P = 0.0111) and lower PMI (P < 0.0001) were identified as significant predictors of poorer OS in our multivariate analysis, while higher serum myostatin (P = 0.0855) tended to be a significant adverse predictor. In both genders, PMI, serum albumin, prothrombin time, and branched-chain amino acid to tyrosine ratio showed a significantly inverse correlation with myostatin levels, and serum ammonia levels showed a significantly positive correlation with myostatin levels.
Conclusions
Higher serum myostatin levels correlated with muscle mass loss, hyperammonemia, and impaired protein synthesis, as reflected by lower serum albumin levels and lower branched-chain amino acid to tyrosine ratio levels. High serum myostatin levels were also associated with a reduced OS rate in LC patients.

 

Nishikawa, H., Enomoto, H., Ishii, A., Iwata, Y., Miyamoto, Y., Ishii, N., Yuri, Y., Hasegawa, K., Nakano, C., Nishimura, T., Yoh, K., Aizawa, N., Sakai, Y., Ikeda, N., Takashima, T., Takata, R., Iijima, H., and Nishiguchi, S. (2017) Elevated serum myostatin level is associated with worse survival in patients with liver cirrhosis. Journal of Cachexia, Sarcopenia and Muscle, 8: 915–925 doi: 10.1002/jcsm.12212.

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     Page 926–938

Jacob L. Brown, Megan E. Rosa-Caldwell, David E. Lee1, Thomas A. Blackwell, Lemuel A. Brown, Richard A. Perry, Wesley S. Haynie, Justin P. Hardee, James A. Carson, Michael P. Wiggs, Tyrone A. Washington, Nicholas P. Greenearks

Mitochondrial degeneration precedes the development of muscle atrophy in progression of cancer cachexia in tumour-bearing miceBackground
Cancer cachexia is largely irreversible, at least via nutritional means, and responsible for 20–40% of cancer-related deaths. Therefore, preventive measures are of primary importance; however, little is known about muscle perturbations prior to onset of cachexia. Cancer cachexia is associated with mitochondrial degeneration; yet, it remains to be determined if mitochondrial degeneration precedes muscle wasting in cancer cachexia. Therefore, our purpose was to determine if mitochondrial degeneration precedes cancer-induced muscle wasting in tumour-bearing mice.
Methods
First, weight-stable (MinStable) and cachectic (MinCC) ApcMin/+ mice were compared with C57Bl6/J controls for mRNA contents of mitochondrial quality regulators in quadriceps muscle. Next, Lewis lung carcinoma (LLC) cells or PBS (control) were injected into the hind flank of C57Bl6/J mice at 8 week age, and tumour allowed to develop for 1, 2, 3, or 4 weeks to examine time course of cachectic development. Succinate dehydrogenase stain was used to measure oxidative phenotype in tibialis anterior muscle. Mitochondrial quality and function were assessed using the reporter MitoTimer by transfection to flexor digitorum brevis and mitochondrial function/ROS emission in permeabilized adult myofibres from plantaris. RT-qPCR and immunoblot measured the expression of mitochondrial quality control and antioxidant proteins. Data were analysed by one-way ANOVA with Student–Newman–Kuels post hoc test.
Results
MinStable mice displayed ~50% lower Pgc-1α, Pparα, and Mfn2 compared with C57Bl6/J controls, whereas MinCC exhibited 10-fold greater Bnip3 content compared with C57Bl6/J controls. In LLC, cachectic muscle loss was evident only at 4 weeks post-tumour implantation. Oxidative capacity and mitochondrial content decreased by ~40% 4 weeks post-tumour implantation. Mitochondrial function decreased by ~25% by 3 weeks after tumour implantation. Mitochondrial degeneration was evident by 2 week LLC compared with PBS control, indicated by MitoTimer red/green ratio and number of pure red puncta. Mitochondrial ROS production was elevated by ~50 to ~100% when compared with PBS at 1–3 weeks post-tumour implantation. Mitochondrial quality control was dysregulated throughout the progression of cancer cachexia in tumour-bearing mice. In contrast, antioxidant proteins were not altered in cachectic muscle wasting.
Conclusions
Functional mitochondrial degeneration is evident in LLC tumour-bearing mice prior to muscle atrophy. Contents of mitochondrial quality regulators across ApcMin/+ and LLC mice suggest impaired mitochondrial quality control as a commonality among pre-clinical models of cancer cachexia. Our data provide novel evidence for impaired mitochondrial health prior to cachectic muscle loss and provide a potential therapeutic target to prevent cancer cachexia.

 

Brown, J. L., Rosa-Caldwell, M. E., Lee, D. E., Blackwell, T. A., Brown, L. A., Perry, R. A., Haynie, W. S., Hardee, J. P., Carson, J. A., Wiggs, M. P., Washington, T. A., and Greene, N. P. (2017) Mitochondrial degeneration precedes the development of muscle atrophy in progression of cancer cachexia in tumour-bearing mice. Journal of Cachexia, Sarcopenia and Muscle, 8: 926–938 doi: 10.1002/jcsm.12232.

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     Page 939–953

Thomas Scott Bowen, Volker Adams, Sarah Werner, Tina Fischer, Paulien Vinke, Maria Noel Brogger, Norman Mangner, Axel Linke, Peter Sehr, Joe Lewis, Dittmar Labeit, Alexander Gasch, Siegfried Labeit

Small-molecule inhibition of MuRF1 attenuates skeletal muscle atrophy and dysfunction in cardiac cachexiaBackground
Muscle ring finger 1 (MuRF1) is a muscle-specific ubiquitin E3 ligase activated during clinical conditions associated with skeletal muscle wasting. Yet, there remains a paucity of therapeutic interventions that directly inhibit MuRF1 function, particularly in vivo. The current study, therefore, developed a novel compound targeting the central coiled coil domain of MuRF1 to inhibit muscle wasting in cardiac cachexia.
Methods
We identified small molecules that interfere with the MuRF1–titin interaction from a 130 000 compound screen based on Alpha Technology. A subset of nine prioritized compounds were synthesized and administrated during conditions of muscle wasting, that is, to C2C12 muscle cells treated with dexamethasone and to mice treated with monocrotaline to induce cardiac cachexia.
Results
The nine selected compounds inhibited MuRF1–titin complexation with IC50 values <25 μM, of which three were found to also inhibit MuRF1 E3 ligase activity, with one further showing low toxicity on cultured myotubes. This last compound, EMBL chemical core ID#704946, also prevented atrophy in myotubes induced by dexamethasone and attenuated fibre atrophy and contractile dysfunction in mice during cardiac cachexia. Proteomic and western blot analyses showed that stress pathways were attenuated by ID#704946 treatment, including down-regulation of MuRF1 and normalization of proteins associated with apoptosis (BAX) and protein synthesis (elF2B-delta). Furthermore, actin ubiquitinylation and proteasome activity was attenuated.
Conclusions
We identified a novel compound directed to MuRF1's central myofibrillar protein recognition domain. This compound attenuated in vivo muscle wasting and contractile dysfunction in cardiac cachexia by protecting de novo protein synthesis and by down-regulating apoptosis and ubiquitin-proteasome-dependent proteolysis.

 

Bowen, T. S., Adams, V., Werner, S., Fischer, T., Vinke, P., Brogger, M. N., Mangner, N., Linke, A., Sehr, P., Lewis, J., Labeit, D., Gasch, A., and Labeit, S. (2017) Small-molecule inhibition of MuRF1 attenuates skeletal muscle atrophy and dysfunction in cardiac cachexia. Journal of Cachexia, Sarcopenia and Muscle, 8: 939–953 doi: 10.1002/jcsm.12233.

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     Page 926–938

Francesca Molinari, Fabrizio Pin, Stefania Gorini, Sergio Chiandotto, Laura Pontecorvo, Fabio Penna, Emanuele Rizzuto,
Simona Pisu, Antonio Musarò, Paola Costelli, Giuseppe Rosano, Elisabetta Ferraro

The mitochondrial metabolic reprogramming agent trimetazidine as an ‘exercise mimetic’ in cachectic C26-bearing miceBackground
Cancer cachexia is characterized by muscle depletion and exercise intolerance caused by an imbalance between protein synthesis and degradation and by impaired myogenesis. Myofibre metabolic efficiency is crucial so as to assure optimal muscle function. Some drugs are able to reprogram cell metabolism and, in some cases, to enhance metabolic efficiency. Based on these premises, we chose to investigate the ability of the metabolic modulator trimetazidine (TMZ) to counteract skeletal muscle dysfunctions and wasting occurring in cancer cachexia.
Methods
For this purpose, we used mice bearing the C26 colon carcinoma as a model of cancer cachexia. Mice received 5 mg/kg TMZ (i.p.) once a day for 12 consecutive days. A forelimb grip strength test was performed and tibialis anterior, and gastrocnemius muscles were excised for analysis. Ex vivo measurement of skeletal muscle contractile properties was also performed.
Results
Our data showed that TMZ induces some effects typically achieved through exercise, among which is grip strength increase, an enhanced fast-to slow myofibre phenotype shift, reduced glycaemia, PGC1a up-regulation, oxidative metabolism, and mitochondrial biogenesis. TMZ also partially restores the myofibre cross-sectional area in C26-bearing mice, while modulation of autophagy and apoptosis were excluded as mediators of TMZ effects.
Conclusions
In conclusion, our data show that TMZ acts like an ‘exercise mimetic’ and is able to enhance some mechanisms of adaptation to stress in cancer cachexia. This makes the modulation of the metabolism, and in particular TMZ, a suitable candidate for a therapeutic rehabilitative protocol design, particularly considering that TMZ has already been approved for clinical use.

 

Molinari, F., Pin, F., Gorini, S., Chiandotto, S., Pontecorvo, L., Penna, F., Rizzuto, E., Pisu, S., Musarò, A., Costelli, P., Rosano, G., and Ferraro, E. (2017) The mitochondrial metabolic reprogramming agent trimetazidine as an ‘exercise mimetic’ in cachectic C26-bearing mice. Journal of Cachexia, Sarcopenia and Muscle, 8: 926–938. doi: 10.1002/jcsm.12226.
 

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     Page 974–990

Tania Cid-Díaz, Icía Santos-Zas, Jessica González-Sánchez, Uxía Gurriarán-Rodríguez, Carlos S. Mosteiro, Xesús Casabiell, Tomás García-Caballero, Vincent Mouly, Yolanda Pazos1, Jesús P. Camiña

Obestatin controls the ubiquitin–proteasome and autophagy–lysosome systems in glucocorticoid-induced muscle cell atrophyBackground
Many pathological states characterized by muscle atrophy are associated with an increase in circulating glucocorticoids and poor patient prognosis, making it an important target for treatment. The development of treatments for glucocorticoid-induced and wasting disorder-related skeletal muscle atrophy should be designed based on how the particular transcriptional program is orchestrated and how the balance of muscle protein synthesis and degradation is deregulated. Here, we investigated whether the obestatin/GPR39 system, an autocrine/paracrine signaling system acting on myogenesis and with anabolic effects on the skeletal muscle, could protect against glucocorticoid-induced muscle cell atrophy.
Methods
In the present study, we have utilized mouse C2C12 myotube cultures to examine whether the obestatin/GPR39 signaling pathways can affect the atrophy induced by the synthetic glucocorticoid dexamethasone. We have extended these findings to in vitro effects on human atrophy using human KM155C25 myotubes.
Results
The activation of the obestatin/GPR39 system protects from glucocorticoid-induced atrophy by regulation of Akt, PKD/PKCµ, CAMKII and AMPK signaling and its downstream targets in the control of protein synthesis, ubiquitin–proteasome system and autophagy–lysosome system in mouse cells. We compared mouse and human myotube cells in their response to glucocorticoid and identified differences in both the triggering of the atrophic program and the response to obestatin stimulation. Notably, we demonstrate that specific patterns of post-translational modifications of FoxO4 and FoxO1 play a key role in directing FoxO activity in response to obestatin in human myotubes.
Conclusions
Our findings emphasize the function of the obestatin/GPR39 system in coordinating a variety of pathways involved in the regulation of protein degradation during catabolic conditions.

 

Cid-Díaz, T., Santos-Zas, I., González-Sánchez, J., Gurriarán-Rodríguez, U., Mosteiro, C. S., Casabiell, X., García-Caballero, T., Mouly, V., Pazos, Y., and Camiña, J. P. (2017) Obestatin controls the ubiquitin–proteasome and autophagy–lysosome systems in glucocorticoid-induced muscle cell atrophy. Journal of Cachexia, Sarcopenia and Muscle, 8: 974–990 doi: 10.1002/jcsm.12222.

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     Page 991–998

Rocco Barazzoni, Gianluca Gortan Cappellari, Sandra Palus, Pierandrea Vinci, Giulia Ruozi, Michela Zanetti, Annamaria Semolic, Nicole Ebner, Stephan von Heahling, Gianfranco Sinagra, Mauro Giacca, Jochen Springer

Acylated ghrelin treatment normalizes skeletal muscle mitochondrial oxidative capacity and AKT phosphorylation in rat chronic heart failureBackground
Chronic heart failure (CHF) is associated with skeletal muscle abnormalities contributing to exercise intolerance, muscle loss, and negative impact on patient prognosis. A primary role has been proposed for mitochondrial dysfunction, which may be induced by systemic and tissue inflammation and further contribute to low insulin signalling. The acylated form of the gastric hormone ghrelin (AG) may improve mitochondrial oxidative capacity and insulin signalling in both healthy and diseased rodent models.
Methods
We investigated the impact of AG continuous subcutaneous administration (AG) by osmotic minipump (50 nmol/kg/day for 28 days) compared with placebo (P) on skeletal muscle mitochondrial enzyme activities, mitochondrial biogenesis regulators transcriptional expression and insulin signalling in a rodent post-myocardial infarction CHF model.
Results
No statistically significant differences (NS) were observed among the three group in cumulative food intake. Compared with sham-operated, P had low mitochondrial enzyme activities, mitochondrial biogenesis regulators transcripts, and insulin signalling activation at AKT level (P < 0.05), associated with activating nuclear translocation of pro-inflammatory transcription factor nuclear factor-?B. AG completely normalized all alterations (P < 0.05 vs P, P = NS vs sham-operated). Direct AG activities were strongly supported by in vitro C2C12 myotubes experiments showing AG-dependent stimulation of mitochondrial enzyme activities. No changes in mitochondrial parameters and insulin signalling were observed in the liver in any group.
Conclusions
Sustained peripheral AG treatment with preserved food intake normalizes a CHF-induced tissue-specific cluster of skeletal muscle mitochondrial dysfunction, pro-inflammatory changes, and reduced insulin signalling. AG is therefore a potential treatment for CHF-associated muscle catabolic alterations, with potential positive impact on patient outcome.

 

 

Barazzoni, R., Gortan Cappellari, G., Palus, S., Vinci, P., Ruozi, G., Zanetti, M., Semolic, A., Ebner, N., von Heahling, S., Sinagra, G., Giacca, M., and Springer, J. (2017) Acylated ghrelin treatment normalizes skeletal muscle mitochondrial oxidative capacity and AKT phosphorylation in rat chronic heart failure. Journal of Cachexia, Sarcopenia and Muscle, 8: 991–998 doi: 10.1002/jcsm.12254.

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     Page 999–1080

Abstracts of the 10th International Conference on Cachexia, Sarcopenia and Muscle Wasting, Rome, Italy, 8–10 December 2017 (Part 1)Abstracts of the 10th International Conference on Cachexia, Sarcopenia and Muscle Wasting, Rome, Italy, 8–10 December 2017 (Part 1)

 

(2017), Abstracts of the 10th International Conference on Cachexia, Sarcopenia and Muscle Wasting, Rome, Italy, 8–10 December 2017 (Part 1). Journal of Cachexia, Sarcopenia and Muscle, 8: 999–1080. doi: 10.1002/jcsm.12255
 

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     Page 1081–1083

Stephan von Haehling, John E. Morley, Andrew J.S. Coats, Stefan D. Anker

Ethical guidelines for publishing in the journal of cachexia, sarcopenia and muscle: update 2017This article details an updated version of the principles of ethical authorship and publishing in the Journal of Cachexia, Sarcopenia and Muscle (JCSM). At the time of submission to JCSM, the corresponding author, on behalf of all co-authors, needs to certify adherence to these principles. The principles are as follows:

 

von Haehling, S., Morley, J. E., Coats, A. J. S., and Anker, S. D. (2017) Ethical guidelines for publishing in the journal of cachexia, sarcopenia and muscle: update 2017. Journal of Cachexia, Sarcopenia and Muscle, 8: 1081–1083. doi: 10.1002/jcsm.12261.

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Thank You to Reviewers     Page 1084–1085

John E. Morley, Stefan D. Anker

With Appreciationno abstract

 

(2017), With Appreciation. Journal of Cachexia, Sarcopenia and Muscle, 8: 1084–1085. doi: 10.1002/jcsm.12263

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