Online First Article

Volume 8 / Number 1 / February 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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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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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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