Volume 7 (2016)

Number 1 / March 2016

 

     Page 34

Stephan von Haehling, Stefan D. Anker

The times they are a-changin’: the Cachexia Conference goes annualno abstract

 

von Haehling, S., and Anker, S. D. (2016) The times they are a-changin’: the Cachexia Conference goes annual. Journal of Cachexia, Sarcopenia and Muscle, 7: 34. doi: 10.1002/jcsm.12110.

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     Page 522

Karin J. C. Sanders, Anita E. M. Kneppers, Coby van de Bool, Ramon C. J. Langen, Annemie M. W. J. Schols

Cachexia in chronic obstructive pulmonary disease: new insights and therapeutic perspectiveCachexia and muscle wasting are well recognized as common and partly reversible features of chronic obstructive pulmonary disease (COPD), adversely affecting disease progression and prognosis. This argues for integration of weight and muscle maintenance in patient care. In this review, recent insights are presented in the diagnosis of muscle wasting in COPD, the pathophysiology of muscle wasting, and putative mechanisms involved in a disturbed energy balance as cachexia driver. We discuss the therapeutic implications of these new insights for optimizing and personalizing management of COPD-induced cachexia.

 

Sanders, K. J. C., Kneppers, A. E. M., van de Bool, C., Langen, R. C. J. and Schols, A. M. W. J. (2015) Cachexia in chronic obstructive pulmonary disease: new insights and therapeutic perspective. Journal of Cachexia, Sarcopenia and Muscle, 7: 522. doi: 10.1002/jcsm.12062.

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     Page 2327

Martin Mücke, Mochamat, Henning Cuhls, Vera Peuckmann-Post, Ollie Minton, Patrick Stone, Lukas Radbruch

Pharmacological treatments for fatigue associated with palliative care: executive summary of a Cochrane Collaboration systematic reviewBackground
In palliative care patients, fatigue can be severely debilitating and is often not counteracted with rest, thereby impacting daily activity and quality of life. Further complicating issues are the multidimensionality, subjective nature and lack of a consensus definition of fatigue. The review aimed to evaluate the efficacy of pharmacological treatments for fatigue in palliative care, with a focus on patients at an advanced stage of disease, including patients with cancer and other chronic diseases.
Methods
We considered randomized controlled trials concerning adult palliative care with a focus on pharmacological treatment of fatigue compared with placebo, application of two drugs, usual care or a non-pharmacological intervention. The primary outcome had to be non-specific fatigue (or related terms such as asthenia). We searched the CENTRAL, MEDLINE, PsycINFO and EMBASE, and a selection of cancer journals up to 28 April 2014. Two review authors independently assessed trial quality and extracted the data.
Results
We screened 1645 publications of which 45 met the inclusion criteria. In total, we analysed data from 18 drugs and 4696 participants. There was a very high degree of statistical and clinical heterogeneity in the trials. Meta-analysis of data was possible for modafinil, pemoline, and methylphenidate.
Conclusions
Due to the limited evidence, we cannot recommend a specific drug for the treatment of fatigue in palliative care patients. Some drugs, which may be beneficial for the treatment of fatigue associated with palliative care such as amantadine, methylphenidate, and modafinil, should be further researched.

 

Mücke, M., Mochamat,, Cuhls, H., Peuckmann-Post, V., Minton, O., Stone, P., and Radbruch, L. (2016) Pharmacological treatments for fatigue associated with palliative care: executive summary of a Cochrane Collaboration systematic review. Journal of Cachexia, Sarcopenia and Muscle, 7: 2327. doi: 10.1002/jcsm.12101.

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     Page 2836

Theodore K. Malmstrom, Douglas K. Miller, Eleanor M. Simonsick, Luigi Ferrucci, John E. Morley

SARC-F: a symptom score to predict persons with sarcopenia at risk for poor functional outcomesBackground
A brief, inexpensive screening test for sarcopenia would be helpful for clinicians and their patients. To screen for persons with sarcopenia, we developed a simple five-item questionnaire (SARC-F) based on cardinal features or consequences of sarcopenia.
Methods
We investigated the utility of SARC-F in the African American Health (AAH) study, Baltimore Longitudinal Study of Aging (BLSA), and National Health and Nutrition Examination Survey (NHANES). Internal consistency reliability for SARC-F was determined using Cronbach's alpha. We evaluated SARC-F factorial validity using principal components analysis and criterion validity by examining its association with exam-based indicators of sarcopenia. Construct validity was examined using cross-sectional and longitudinal differences among those with high (≥4) vs. low (<4) SARC-F scores for mortality and health outcomes.
Results
SARC-F exhibited good internal consistency reliability and factorial, criterion, and construct validity. AAH participants with SARC-F scores ≥ 4 had more Instrumental Activity of Daily Living (IADL) deficits, slower chair stand times, lower grip strength, lower short physical performance battery scores, and a higher likelihood of recent hospitalization and of having a gait speed of <0.8 m/s. SARC-F scores ≥ 4 in AAH also were associated with 6 year IADL deficits, slower chair stand times, lower short physical performance battery scores, having a gait speed of <0.8 m/s, being hospitalized recently, and mortality. SARC-F scores ≥ 4 in the BLSA cohort were associated with having more IADL deficits and lower grip strength (both hands) in cross-sectional comparisons and with IADL deficits, lower grip strength (both hands), and mortality at follow-up. NHANES participants with SARC-F scores ≥ 4 had slower 20 ft walk times, had lower peak force knee extensor strength, and were more likely to have been hospitalized recently in cross-sectional analyses.
Conclusions
The SARC-F proved internally consistent and valid for detecting persons at risk for adverse outcomes from sarcopenia in AAH, BLSA, and NHANES.

 

Malmstrom, T. K., Miller, D. K., Simonsick, E. M., Ferrucci, L., and Morley, J. E. (2015) SARC-F: a symptom score to predict persons with sarcopenia at risk for poor functional outcomes. Journal of Cachexia, Sarcopenia and Muscle, 7: 2836. doi: 10.1002/jcsm.12048.

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     Page 3747

Miguel L. Batista Jr., Felipe S. Henriques, Rodrigo X. Neves, Mireia R. Olivan, Emídio M. Matos-Neto, Paulo S. M. Alcântara, Linda F. Maximiano, José P. Otoch, Michele J. Alves, Marília Seelaender

Cachexia-associated adipose tissue morphological rearrangement in gastrointestinal cancer patientsBackground and aims
Cachexia is a syndrome characterized by marked involuntary loss of body weight. Recently, adipose tissue (AT) wasting has been shown to occur before the appearance of other classical cachexia markers. We investigated the composition and rearrangement of the extracellular matrix, adipocyte morphology and inflammation in the subcutaneous AT (scAT) pad of gastrointestinal cancer patients.
Methods
Surgical biopsies for scAT were obtained from gastrointestinal cancer patients, who were signed up into the following groups: cancer cachexia (CC, n = 11), weight-stable cancer (WSC, n = 9) and weight-stable control (non-cancer) (control, n = 7). The stable weight groups were considered as those with no important weight change during the last year and body mass index <25 kg/m2. Subcutaneous AT fibrosis was quantified and characterized by quantitative PCR, histological analysis and immunohistochemistry.
Results
The degree of fibrosis and the distribution and collagen types (I and III) were different in WSC and CC patients. CC patients showed more pronounced fibrosis in comparison with WSC. Infiltrating macrophages surrounding adipocytes and CD3 Ly were found in the fibrotic areas of scAT. Subcutaneous AT fibrotic areas demonstrated increased monocyte chemotactic protein 1 (MCP-1) and Cluster of Differentiation (CD)68 gene expression in cancer patients.
Conclusions
Our data indicate architectural modification consisting of fibrosis and inflammatory cell infiltration in scAT as induced by cachexia in gastrointestinal cancer patients. The latter was characterized by the presence of macrophages and lymphocytes, more evident in the fibrotic areas. In addition, increased MCP-1 and CD68 gene expression in scAT from cancer patients may indicate an important role of these markers in the early phases of cancer.

 

Batista, Jr. M. L., Henriques, F. S., Neves, R. X., Olivan, M. R., Matos-Neto, E. M., Alcântara, P. S. M., Maximiano, L. F., Otoch, J. P., Alves, M. J., and Seelaender, M. (2015), Cachexia-associated adipose tissue morphological rearrangement in gastrointestinal cancer patients. Journal of Cachexia, Sarcopenia and Muscle, 7: 3747. doi: 10.1002/jcsm.12037.

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     Page 4859

Míriam Toledo, Fabio Penna, Francesc Oliva, Melania Luque, Angelica Betancourt, Enrica Marmonti, Francisco J. López-Soriano, Josep M. Argilés, Sílvia Busquets

A multifactorial anti-cachectic approach for cancer cachexia in a rat model undergoing chemotherapyBackground
The effectiveness of drugs aimed at counteracting cancer cachexia is generally tested in pre-clinical rodent models, where only the tumour-induced alterations are taken into account, excluding the co-presence of anti-tumour molecules that could worsen the scenario and/or interfere with the treatment.
Methods
The aim of the present investigation has been to assess the efficacy of a multifactorial treatment, including formoterol and megestrol acetate, in cachectic tumour-bearing rats (Yoshida AH-130, a highly cachectic tumour) undergoing chemotherapy (sorafenib).
Results
Treatment of cachectic tumour-bearing rats with sorafenib (90 mg/kg) causes an important decrease in tumour cell content due to both reduced cell proliferation and increased apoptosis. As a consequence, animal survival significantly improves, while cachexia occurrence persists. Multi-factorial treatment using both formoterol and megestrol acetate is highly effective in preventing muscle wasting and has more powerful effects than the single formoterol administration. In addition, both physical activity and grip strength are significantly improved as compared with the untreated tumour-bearing animals. The effects of the multi-factorial treatment include increased food intake (likely due to megestrol acetate) and decreased protein degradation, as shown by the reduced expression of genes associated with both proteasome and calpain proteolytic systems.
Conclusions
The combination of the two drugs proved to be a promising strategy for treating cancer cachexia in a pre-clinical setting that better resembles the human condition, thus providing a strong rationale for the use of such combination in clinical trials involving cachectic cancer patients.
 
 
Toledo, M., Penna, F., Oliva, F., Luque, M., Betancourt, A., Marmonti, E., López-Soriano, F. J., Argilés, J. M., and Busquets, S. (2015), A multifactorial anti-cachectic approach for cancer cachexia in a rat model undergoing chemotherapy. Journal of Cachexia, Sarcopenia and Muscle, 7: 4859. doi: 10.1002/jcsm.12035.

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     Page 6067

Nadja Scherbakov, Michael Knops, Nicole Ebner, Miroslava Valentova, Anja Sandek, Ulrike Grittner, Pius Dahinden, Stefan Hettwer, Jörg C Schefold, Stephan von Haehling, Stefan D. Anker, Michael Joebges, Wolfram Doehner

Evaluation of C-terminal Agrin Fragment as a marker of muscle wasting in patients after acute stroke during early rehabilitationBackground
C-terminal Agrin Fragment (CAF) has been proposed as a novel biomarker for sarcopenia originating from the degeneration of the neuromuscular junctions. In patients with stroke muscle wasting is a common observation that predicts functional outcome. We aimed to evaluate agrin sub-fragment CAF22 as a marker of decreased muscle mass and physical performance in the early phase after acute stroke.
Methods
Patients with acute ischaemic or haemorrhagic stroke (n = 123, mean age 70 ± 11 y, body mass index BMI 27.0 ± 4.9 kg/m2) admitted to inpatient rehabilitation were studied in comparison to 26 healthy controls of similar age and BMI. Functional assessments were performed at begin (23 ± 17 days post stroke) and at the end of the structured rehabilitation programme (49 ± 18 days post stroke) that included physical assessment, maximum hand grip strength, Rivermead motor assessment, and Barthel index. Body composition was assessed by bioelectrical impedance analysis (BIA). Serum levels of CAF22 were measured by ELISA.
Results
CAF22 levels were elevated in stroke patients at admission (134.3 ± 52.3 pM) and showed incomplete recovery until discharge (118.2 ± 42.7 pM) compared to healthy controls (95.7 ± 31.8 pM, p < 0.001). Simple regression analyses revealed an association between CAF22 levels and parameters of physical performance, hand grip strength, and phase angle, a BIA derived measure of the muscle cellular integrity. Improvement of the handgrip strength of the paretic arm during rehabilitation was independently related to the recovery of CAF22 serum levels only in those patients who showed increased lean mass during the rehabilitation.
Conclusions
CAF22 serum profiles showed a dynamic elevation and recovery in the subacute phase after acute stroke. Further studies are needed to explore the potential of CAF22 as a serum marker to monitor the muscle status in patients after stroke.

 

Scherbakov, N., Knops, M., Ebner, N., Valentova, M., Sandek, A., Grittner, U., Dahinden, P., Hettwer, S., Schefold, J. C., von Haehling, S., Anker, S. D., Joebges, M., and Doehner, W. (2015) Evaluation of C-terminal Agrin Fragment as a marker of muscle wasting in patients after acute stroke during early rehabilitation. Journal of Cachexia, Sarcopenia and Muscle, 7: 6067. doi: 10.1002/jcsm.12068.

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     Page 6878

María D. Girón, José D. Vílchez, Rafael Salto, Manuel Manzano, Natalia Sevillano, Nefertiti Campos, Josep M. Argilés, Ricardo Rueda, José M. López-Pedros

Conversion of leucine to β-hydroxy-β-methylbutyrate by α-keto isocaproate dioxygenase is required for a potent stimulation of protein synthesis in L6 rat myotubesBackground
L-Leu and its metabolite β-hydroxy-β-methylbutyrate (HMB) stimulate muscle protein synthesis enhancing the phosphorylation of proteins that regulate anabolic signalling pathways. Alterations in these pathways are observed in many catabolic diseases, and HMB and L-Leu have proven their anabolic effects in in vivo and in vitro models. The aim of this study was to compare the anabolic effects of L-Leu and HMB in myotubes grown in the absence of any catabolic stimuli.
Methods
Studies were conducted in vitro using rat L6 myotubes under normal growth conditions (non-involving L-Leu-deprived conditions). Protein synthesis and mechanistic target of rapamycin signalling pathway were determined.
Results
Only HMB was able to increase protein synthesis through a mechanism that involves the phosphorylation of the mechanistic target of rapamycin as well as its downstream elements, pS6 kinase, 4E binding protein-1, and eIF4E. HMB was significantly more effective than L-Leu in promoting these effects through an activation of protein kinase B/Akt. Because the conversion of L-Leu to HMB is limited in muscle, L6 cells were transfected with a plasmid that codes for α-keto isocaproate dioxygenase, the key enzyme involved in the catabolic conversion of α-keto isocaproate into HMB. In these transfected cells, L-Leu was able to promote protein synthesis and mechanistic target of rapamycin regulated pathway activation equally to HMB. Additionally, these effects of leucine were reverted to a normal state by mesotrione, a specific inhibitor of α-keto isocaproate dioxygenase.
Conclusion
Our results suggest that HMB is an active L-Leu metabolite able to maximize protein synthesis in skeletal muscle under conditions, in which no amino acid deprivation occurred. It may be proposed that supplementation with HMB may be very useful to stimulate protein synthesis in wasting conditions associated with chronic diseases, such as cancer or chronic heart failure.
 
 
 
Girón, M. D., Vílchez, J. D., Salto, R., Manzano, M., Sevillano, N., Campos, N., Argilés, J. M., Rueda, R., and López-Pedrosa, J. M. (2015), Conversion of leucine to β-hydroxy-β-methylbutyrate by α-keto isocaproate dioxygenase is required for a potent stimulation of protein synthesis in L6 rat myotubes. Journal of Cachexia, Sarcopenia and Muscle, 7: 6878. doi: 10.1002/jcsm.12032.

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     Page 7989

Ana Belen Gómez-SanMiguel, Ana Isabel Martín, María Paz Nieto-Bona, Carmen Fernández-Galaz, María Ángeles Villanúa, Asunción López-Calderón

The melanocortin receptor type 3 agonist d-Trp(8)-γMSH decreases inflammation and muscle wasting in arthritic ratsBackground
Chronic inflammatory diseases induce cachexia that increases mortality and morbidity of the illness. Adjuvant-induced arthritis is an experimental model of rheumatoid arthritis that is associated with body weight loss and muscle wasting. Alpha-melanocyte stimulating hormone has an anti-inflammatory effect in arthritic rats and decreases muscle wasting. The aim of this work was to elucidate whether the anti-cachectic action of alpha-melanocyte stimulating hormone is mediated by the melanocortin receptor type 3 pathway.
Methods
Arthritis was induced in male Wistar rats by intradermal injection of Freund's adjuvant, and 6 days afterwards, arthritic rats were injected with the selective melanocortin receptor type 3 agonist d-Trp(8)-gammaMSH ( d-Trp(8)-γMSH) 500 µg/kg subcutaneously. or saline twice a day, for 10 days.
Results
d-Trp(8)-γMSH decreased the external signs of inflammation and body weight loss, but it was not able to modify the anorexigenic effect of arthritis or the increase in hypothalamic cyclooxygenase-2 (COX-2) expression. In contrast, d-Trp(8)-γMSH prevented arthritis-induced increase in hypothalamic IL-1β and serum corticosterone levels and the decrease in serum IGF-I levels. d-Trp(8)-γMSH treatment also prevented arthritis-induced NF-kB(p65) phosphorylation and tumour necrosis factor-α mRNA increase in the gastrocnemius. d-Trp(8)-γMSH administration to arthritic rats increased gastrocnemius mass, its cross-sectional area, and mean fast fibre area. Those effects of d-Trp(8)-γMSH were associated with a decreased expression of atrogin-1 and muscle ring-finger protein-1 in the gastrocnemius. In rats treated with saline, arthritis increased the expression of autophagy marker genes LC3b, Bnip-3, and Gabarap1 as well as the conversion of LC3b I to LC3b II by lipidation in the gastrocnemius. d-Trp(8)-γMSH decreased gastrocnemius LC3b, Bnip-3, and Gabarap1 mRNA expression and prevented the increase in LC3b II in arthritic rats.
Conclusion
These data suggest that d-Trp(8)-γMSH administration prevents the effect of arthritis on corticosterone and insulin-like growth factor-I serum levels and decreases muscle wasting, by down-regulating atrogenes and autophagy through modifying the NF-kB(p65)/tumour necrosis factor-α signalling transduction pathway.
 
 
Gómez-SanMiguel, A. B., Martín, A. I., Nieto-Bona, M. P., Fernández-Galaz, C., Villanúa, M. Á., and López-Calderón, A. (2015), The melanocortin receptor type 3 agonist d-Trp(8)-γMSH decreases inflammation and muscle wasting in arthritic rats. Journal of Cachexia, Sarcopenia and Muscle, 7: 7989. doi: 10.1002/jcsm.12036.

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     Page 9094

Nicole Ebner, Stephan von Haehling

Unlocking the wasting enigma: Highlights from the 8th Cachexia ConferenceThis article highlights pre-clinical and clinical studies into the field of wasting disorders that were presented at the 8th Cachexia Conference held in Paris, France December 2015. This year some interesting results of clinical trials and different new therapeutic targets were shown. This article presents the biological and clinical significance of different markers and new drugs for the treatment of skeletal muscle wasting. Effective treatments of cachexia and wasting disorders are urgently needed in order to improve the patients' quality of life and their survival.

 

Ebner, N., and von Haehling, S. (2016) Unlocking the wasting enigma: Highlights from the 8th Cachexia Conference. Journal of Cachexia, Sarcopenia and Muscle, 7: 9094. doi: 10.1002/jcsm.12106.

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     Page 9596

Hidetaka Wakabayashi, Naoko Watanabe, Mami Anraku, Hideyuki Oritsu, Yoshitaka Shimizu

Pre-operative psoas muscle mass and post-operative gait speed following total hip arthroplasty for osteoarthritisNo abstract

 

Wakabayashi, H., Watanabe, N., Anraku, M., Oritsu, H., and Shimizu, Y. (2015) Pre-operative psoas muscle mass and post-operative gait speed following total hip arthroplasty for osteoarthritis. Journal of Cachexia, Sarcopenia and Muscle, 7: 9596. doi: 10.1002/jcsm.12046.

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     Page 9799

Seyyed Mohammad Reza Kazemi-Bajestani, Harald Becher, Sunita Ghosh, Aldo J. Montano-Loza, Vickie E Baracos

Concurrent depletion of skeletal muscle, fat, and left ventricular mass in patients with cirrhosis of the liverno abstract

 

Kazemi-Bajestani, S. M. R., Becher, H., Ghosh, S., Montano-Loza, A. J., and Baracos, V. E. (2015) Concurrent depletion of skeletal muscle, fat, and left ventricular mass in patients with cirrhosis of the liver. Journal of Cachexia, Sarcopenia and Muscle, 7: 9799. doi: 10.1002/jcsm.12093.

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     Page 100101

Nadja Scherbakov, Wolfram Doehner

Searching for a relevant definition of sarcopenia: results from the cross-sectional EPIDOS studyno abstract

 

Scherbakov, N., and Doehner, W. (2015) Searching for a relevant definition of sarcopenia: results from the cross-sectional EPIDOS study. Journal of Cachexia, Sarcopenia and Muscle, 7: 100101. doi: 10.1002/jcsm.12090.

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     Page 102104

With Appreciationno abstract

 

(2016), With Appreciation. Journal of Cachexia, Sarcopenia and Muscle, 7: 102–104. doi: 10.1002/jcsm.12114

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Number 2 / May 2016

 

      Page 115124

John P. Sasso,Neil D. Eves,Jesper F. Christensen,Graeme J. Koelwyn,Jessica Scott, Lee W. Jones

A framework for prescription in exercise-oncology researchThe field of exercise-oncology has increased dramatically over the past two decades, with close to 100 published studies investigating the efficacy of structured exercise training interventions in patients with cancer. Of interest, despite considerable differences in study population and primary study end point, the vast majority of studies have tested the efficacy of an exercise prescription that adhered to traditional guidelines consisting of either supervised or home-based endurance (aerobic) training or endurance training combined with resistance training, prescribed at a moderate intensity (50–75% of a predetermined physiological parameter, typically age-predicted heart rate maximum or reserve), for two to three sessions per week, for 10 to 60 min per exercise session, for 12 to 15 weeks. The use of generic exercise prescriptions may, however, be masking the full therapeutic potential of exercise treatment in the oncology setting. Against this background, this opinion paper provides an overview of the fundamental tenets of human exercise physiology known as the principles of training, with specific application of these principles in the design and conduct of clinical trials in exercise-oncology research. We contend that the application of these guidelines will ensure continued progress in the field while optimizing the safety and efficacy of exercise treatment following a cancer diagnosis.
 
 
Sasso, J. P., Eves, N. D., Christensen, J. F., Koelwyn, G. J., Scott, J., and Jones, L. W. (2015), A framework for prescription in exercise-oncology research. Journal of Cachexia, Sarcopenia and Muscle, 6, 115124.

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      Page 125 - 131

Sitaramachandra M. Nyasavajjala, Beth E. Phillips, Jon N. Lund, John P. Williams

Creatinine and myoglobin are poor predictors of anaerobic threshold in colorectal cancer and health
Aims

Myoglobin is a haem protein produced in skeletal muscles. Serum concentrations of myoglobin have been proposed as a surrogate marker of muscle mass and function in both cachectic cancer patients and healthy non-cancer individuals. Creatinine, a metabolite of creatine phosphate, an energy store found in skeletal muscle, is produced at a constant rate from skeletal muscle. Urinary and plasma creatinine have been used in clinical practice as indicators of skeletal muscle mass in health and disease. Our study aimed to test the hypothesis that plasma myoglobin and creatinine concentration could accurately predict skeletal muscle mass and aerobic capacity in colorectal cancer (CRC) patients and matched healthy controls and thereby an indicative of aerobic performance.

Methods

We recruited 47 patients with CRC and matching number of healthy volunteers for this study. All participants had their body composition measured by dual-energy X-ray absorptiometry scan, aerobic capacity measured to anaerobic threshold (AT) by cardiopulmonary exercise testing and filled in objective questionnaires to assess the qualitative functions. This study was carried out in accordance with the Declaration of Helsinki, after approval by the local National Health Service (NHS) Research Ethics Committee.

Results

Age-matched groups had similar serum myoglobin and creatinine concentrations in spite of differences in their aerobic capacity. AT was significantly lower in the CRC group compared with matched controls (1.18 ± 0.44 vs. 1.41 ± 0.71 L/min; P < 0.01). AT had significant correlation with lean muscle mass (LMM) among these groups, but myoglobin and creatinine had poor correlation with LMM and AT.

Conclusions

Serum myoglobin is a poor predictor of muscle mass, and serum myoglobin and creatinine concentrations do not predict aerobic performance in CRC patients or healthy matched controls.

 

Nyasavajjala, S. M., Phillips, B. E., Lund, J. N., Williams, J. P. (2015), Creatinine and myoglobin are poor predictors of anaerobic threshold in colorectal cancer and health. Journal of Cachexia, Sarcopenia and Muscle, 6, 125131

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      Page 132143

Ji-an Chen, Andres Splenser, Bobby Guillory, Jiaohua Luo, Meenal Mendiratta, Blaga Belinova, Tripti Halder, Guohua Zhang, Yi-Ping Li, Jose M. Garcia

Ghrelin prevents tumour- and cisplatin-induced muscle wasting: characterization of multiple mechanisms involved
Background

A higher serum phosphate level is associated with worse outcome. Energy-demanding intracellular transport of phosphate is needed to secure anion bioavailability. In heart failure (HF), energy starvation may modify intracellular and serum levels of phosphate. We analysed determinants of serum phosphates in HF and assessed if catabolic/anabolic balance (CAB) was associated with elevation of serum phosphate.

Methods

We retrospectively reviewed data from 1029 stable patients with HF and have calculated negative (loss) and positive (gain) components of weight change from the onset of HF till index date. The algebraic sum of these components was taken as CAB. The univariate and multivariable predictors of serum phosphorus were calculated. In quintiles of CAB, we have estimated odds ratios for serum phosphorus above levels previously identified to increase risk of mortality. As a reference, we have selected a CAB quintile with similar loss and gain.

Results

Apart from sex, age, and kidney function, we identified serum sodium, N-terminal fragment of pro-brain-type natriuretic peptide, and CAB as independent predictors of serum phosphorus. The odds for serum phosphorus above thresholds found in literature to increase risk were highest in more catabolic patients. In most catabolic quintile relative to neutral balance, the odds across selected phosphorus thresholds rose, gradually peaking at 1.30 mmol/L with a value of 3.29 (95% confidence interval: 2.00–5.40, P < 0.0001) in an unadjusted analysis and 2.55 (95% confidence interval: 1.38–2.72, P = 0.002) in a fully adjusted model.

Conclusions

Metabolic status is an independent determinant of serum phosphorus in HF. Higher catabolism is associated with serum phosphorus above mortality risk-increasing thresholds.
 
 
Chen, J.-a., Splenser, A., Guillory, B., Luo, J., Mendiratta, M., Belinova, B., Halder, T., Zhang, G., Li, Y.-P., and Garcia, J. M. (2015), Ghrelin prevents tumour- and cisplatin-induced muscle wasting: characterization of multiple mechanisms involved. Journal of Cachexia Sarcopenia Muscle, 6, 132143.

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       Page 144154

Charlotte Dupuy, Valérie Lauwers-Cances, Sophie Guyonnet, Catherine Gentil, Gabor Abellan Van Kan, Olivier Beauchet, Anne-Marie Schott, Bruno Vellas, Yves Rolland

Searching for a relevant definition of sarcopenia: results from the cross-sectional EPIDOS study
Background

The diversity of definitions proposed for sarcopenia has been rarely tested in the same population, and so far, their clinical utilities for predicting physical difficulties could not be clearly understood. Our objective is to report the prevalence of sarcopenia and the characteristics of sarcopenic community-dwelling older women according to the different definitions of sarcopenia currently proposed. We also assessed these definitions for their incremental predictive value over currently standard predictors for some self-reported difficulties in physical function and knee extension strength.

Methods

Cross-sectional analysis included data from 3025 non-disabled women aged 75 years or older without previous history of hip fracture from the inclusion visit of the EPIDémiologie de l'OStéoporose study. A total body composition evaluation was available for 2725 women. Sarcopenia was defined using six different definitions of sarcopenia based on different muscle mass, gait speed, and grip strength cut-offs. Self-reported difficulties in physical function and knee extension strength were collected. Logistic regression and multiple linear regression models were built for each physical dysfunction, and the predictive capacity of sarcopenia (one model for each definition) was studied using the C-statistic, the net reclassification index, or adjusted R2.

Results

The estimated prevalence of sarcopenia ranged from 3.3–20.0%. Only 85 participants (3.1%) were identified having sarcopenia according to all definitions. All definitions were, to some degree, associated with self-reported difficulties in physical function and knee extension strength, but none improved the predictive ability of the self-reported difficulties in physical function. Conversely, all definitions accounted for a small but significant amount of explained variation for predicting knee extension strength.

Conclusions

Prevalence of sarcopenia varies widely depending on the definition adopted. Based on this research, the current definitions for sarcopenia does not substantially increment the predictive value of clinical characteristics of patients to predict self-reported physical difficulties and knee extension strength.

 

Dupuy, C., Lauwers-Cances, V., Guyonnet, S., Gentil, C., Abellan Van Kan, G., Beauchet, O., Schott, A.-M., Vellas, B., and Rolland, Y. (2015), Searching for a relevant definition of sarcopenia: results from the cross-sectional EPIDOS study. Journal Cachexia Sarcopenia Muscle, 6, 144154.

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       Page 155163

Toine M. Lodewick, Anjali A.J. Roeth, Steven W.M. Olde Damink, Patrick H. Alizai, Ronald M. van Dam, Nikolaus Gassler, Mark Schneider, Simon A.W.G. Dello, Maximilian Schmeding, Cornelis H.C. Dejong, Ulf P. Neumann

Sarcopenia, obesity and sarcopenic obesity  effects on liver function and volume in patients scheduled for major liver resection
Background

Sarcopenia, obesity and sarcopenic obesity have been linked to impaired outcome after liver surgery. Preoperative liver function of sarcopenic, obese and sarcopenic-obese patients might be reduced, possibly leading to more post-operative morbidity. The aim of this study was to explore whether liver function and volume were influenced by body composition in patients undergoing liver resection.

Methods

In 2011 and 2012, all consecutive patients undergoing the methacetin breath liver function test were included. Liver volumetry and muscle mass analysis were performed using preoperative CT scans and Osirix® software. Muscle mass and body-fat% were calculated. Predefined cut-off values for sarcopenia and the top two body-fat% quintiles were used to identify sarcopenia and obesity, respectively. Histologic assessment of the resected liver gave insight in background liver disease.

Results

A total number of 80 patients were included. Liver function and volume were comparable in sarcopenic(-obese) and non-sarcopenic(-obese) patients. Obese patients showed significantly reduced liver function [295 (95–508) vs. 358 (96–684) µg/kg/h, P = 0.018] and a trend towards larger liver size [1694 (1116–2685) vs. 1533 (869–2852) mL, P = 0.079] compared with non-obese patients. Weight (r = −0.40), body surface area (r = −0.32), estimated body-fat% (r = −0.43) and body mass index (r = −0.47) showed a weak but significant negative (all P  < 0.05) correlation with liver function. Moreover, body-fat% was identified as an independent factor negatively affecting the liver function.

Conclusion

Sarcopenia and sarcopenic obesity did not seem to influence liver size and function negatively. However, obese patients had larger, although less functional, livers, indicating dissociation of liver function and volume in these patients.

 

Lodewick, T. M., Roeth, A. A., Olde Damink, S. W., Alizai, P. H., van Dam, R. M., Gassler, N., Schneider, M., Dello, S. A., Schmeding, M., Dejong, C. H., Neumann, U. P. (2015), Sarcopenia, obesity and sarcopenic obesity: effects on liver function and volume in patients scheduled for major liver resection. Journal of Cachexia, Sarcopenia and Muscle, 6, 155163.

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       Page 164173

Piotr Rozentryt, Jacek T. Niedziela, Bartosz Hudzik, Andrzej Lekston, Wolfram Doehner, Ewa A. Jankowska, Jolanta Nowak, Stephan von Haehling, Robert Partyka, Tomasz Rywik, Stefan D. Anker, Piotr Ponikowski, Lech Poloński

Preserved muscle oxidative metabolic phenotype in newly diagnosed non-small cell lung cancer cachexia
Background

Cachexia augments cancer-related mortality and has devastating effects on quality of life. Pre-clinical studies indicate that systemic inflammation-induced loss of muscle oxidative phenotype (OXPHEN) stimulates cancer-induced muscle wasting. The aim of the current proof of concept study is to validate the presence of muscle OXPHEN loss in newly diagnosed patients with lung cancer, especially in those with cachexia.

Methods

Quadriceps muscle biopsies of comprehensively phenotyped pre-cachectic (n = 10) and cachectic (n = 16) patients with non-small cell lung cancer prior to treatment were compared with healthy age-matched controls (n  = 22). OXPHEN was determined by assessing muscle fibre type distribution (immunohistochemistry), enzyme activity (spectrophotometry), and protein expression levels of mitochondrial complexes (western blot) as well as transcript levels of (regulatory) oxidative genes (quantitative real-time PCR). Additionally, muscle fibre cross-sectional area (immunohistochemistry) and systemic inflammation (multiplex analysis) were assessed.

Results

Muscle fibre cross-sectional area was smaller, and plasma levels of interleukin 6 were significantly higher in cachectic patients compared with non-cachectic patients and healthy controls. No differences in muscle fibre type distribution or oxidative and glycolytic enzyme activities were observed between the groups. Mitochondrial protein expression and gene expression levels of their regulators were also not different.

Conclusion

Muscle OXPHEN is preserved in newly diagnosed non-small cell lung cancer and therefore not a primary trigger of cachexia in these patients.

 

Op den Kamp, C. M., Gosker, H. R., Lagarde, S., Tan, D. Y., Snepvangers, F. J., Dingemans, A. C. C., Langen, R. C., and Schols, A. M. (2015), Preserved muscle oxidative metabolic phenotype in newly diagnosed non-small cell lung cancer cachexia. Journal of Cachexia, Sarcopenia and Muscle, 6, 164173.

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       Page 174180

Masaaki Konishi, Loes Pelgrim, Anika Tschirner, Anna Baumgarten, Stephan von Haehling, Sandra Palus, Wolfram Doehner, Stefan D. Anker, Jochen Springer

Febuxostat improves outcome in a rat model of cancer cachexiaBackground

Activity of xanthine oxidase is induced in cancer cachexia, and its inhibition by allopurinol or oxypurinol improves survival and reduces wasting in the Yoshida hepatoma cancer cachexia model. Here, we tested the effects of the second-generation xanthine oxidase inhibitor febuxostat compared with placebo in the same model as used previously by our group.

Methods

Wistar rats (~200 g) were treated daily with febuxostat at 5 mg/kg/day or placebo via gavage for a maximum of 17 days. Weight change, quality of life, and body composition were analysed. After sacrifice, proteasome activity in the gastrocnemius muscle was measured. Muscle-specific proteins involved in metabolism were analysed by western blotting.

Results

Treatment of the tumour-bearing rats with febuxostat led to a significantly improved survival compared with placebo (hazard ratio: 0.45, 95% confidence interval: 0.22–0.93, P = 0.03). Loss of body weight was reduced (−26.3 ± 12.4 g) compared with placebo (−50.2 ± 2.1 g, P < 0.01). Wasting of lean mass was attenuated (−12.7 ± 10.8 g) vs. placebo (−31.9 ± 2.1 g, P  < 0.05). While we did not see an effect of febuxostat on proteasome activity at the end of the study, the pAkt/Akt ratio was improved by febuxostat (0.94 ± 0.09) vs. placebo (0.41 ± 0.05, P < 0.01), suggesting an increase in protein synthesis.

Conclusions

Febuxostat attenuated cachexia progression and improved survival of tumour-bearing rats.

 

Konishi, M., Pelgrim, L., Tschirner, A., Baumgarten, A., von Haehling, S., Palus, S., Doehner, W., Anker, S. D., and Springer, J. (2015), Febuxostat improves outcome in a rat model of cancer cachexia. Journal of Cachexia, Sarcopenia and Muscle, 6, 174180.

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       Page 181191

Robert Kob,Claudia Fellner,Thomas Bertsch,Astrid Wittmann,Daria Mishura,Cornel C. Sieber,Barbara E. Fischer,Christian Stroszczynski, Cornelius L. Bollheimer

Gender-specific differences in the development of sarcopenia in the rodent model of the ageing high-fat ratBackground

Sarcopenia is linked to functional impairments, loss of independence, and mortality. In the past few years, obesity has been established as being a risk factor for a decline in muscle mass and function. There are several molecular pathological mechanisms, which have been under discussion that might explain this relationship. However, most studies were conducted using male animals and for a short period of time.

Methods

In this study, the gender-specific effect of long-term, high-fat content feeding in Sprague–Dawley rats was examined. Development of the quadriceps muscle of the animals was monitored in vivo using magnetic resonance. The results of these measurements and of the biochemical analysis of the aged muscle were compared.

Results

Surprisingly, only male but not female rats showed a decline in muscle cross-sectional area at 16 months of age as a result of a chronic oversupply of dietary fats. This loss of muscle mass could not be explained by either de-regulation of the anabolic Akt pathway or by up-regulation of the main ubiquitin ligases of muscle, MAFbx and MuRF-1. However, fusion of satellite cells to myotubes was induced by the high-fat diet in male rats, possibly as a result of an increased need for compensatory regeneration processes. Caspase-3-dependent apoptosis induction, irrespective of diet, seems to be the major determinant of muscle decline during ageing in male but not female rats.

Conclusion

Taken together, activation of the apoptosis-inducing Caspase-3 seems to be the most important trigger for the age-related muscle loss. Male rats were more prone to the decline of muscle during ageing than female animals, which was further enforced by a long-term, high fat diet.

 

Kob, R., Fellner, C., Bertsch, T., Wittmann, A., Mishura, D., Sieber, C. C., Fischer, B. E., Stroszczynski, C., and Bollheimer, C. L. (2015), Gender-specific differences in the development of sarcopenia in the rodent model of the ageing high-fat rat. Journal of Cachexia, Sarcopenia and Muscle, 6, 181–191.

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       Page 192

Xiao-Hui Sun, Hai-Zhu Yu*, Meng-Meng Yang, Yi-Meng Yang, Zhi-Min Dang

CorrigendumNo abstract

 

This article corrects:

The affiliation of the authors Anker and von Haehling was rendered wrongly in the following papers: Morley et al. (2014), and Anker and von Haehling (2014), and for Anker and Springer in Toledo et al. (2014), and Cvan Trobec et al. (2015).

The correct affiliation is as given here:

Division of Innovative Clinical Trials, Department of Cardiology and Pneumology, University Medical Centre Göttingen, Göttingen, Germany.

Sun, X.-H., Yu, H.-Z., Yang, M.-M., Yang, Y.-M., and Dang, Z.-M. (2015), Corrigendum. Journal of Cachexia, Sarcopenia and Muscle, 6, 192.

 

 

 
Number 3 / June 2016

 

     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 / September 2016

 

     Page 391395

Stephan von Haehling, Nicole Ebner, Stefan D. Anker

Moving upwards – the journal of cachexia, sarcopenia and muscle in 2016no abstract

 

von Haehling, S., Ebner, N., and Anker, S. D. (2016) Moving upwards – the journal of cachexia, sarcopenia and muscle in 2016. Journal of Cachexia, Sarcopenia and Muscle, 7: 391–395. doi: 10.1002/jcsm.12142.

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     Page 396399

Maciej Banach, Maria-Corina Serban

Discussion around statin discontinuation in older adults and patients with wasting diseasesno abstract

 

Banach, M., and Serban, M. -C. (2016) Discussion around statin discontinuation in older adults and patients with wasting diseases. Journal of Cachexia, Sarcopenia and Muscle, 7: 396399. doi: 10.1002/jcsm.12109.

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     Page 400402

Mitja Lainscak, Alessandro Laviano

ACT-ONE - ACTION at last on cancer cachexia by adapting a novel action beta-blockerNovel action beta-blockers combine many different pharmacological effects. The espindolol exhibits effects through β and central 5-HT1α receptors to demonstrate pro-anabolic, anti-catabolic, and appetite-stimulating actions. In the ACT-ONE trial, espindolol reversed weight loss and improved handgrip strength in patients with cachexia due to non-small cell lung cancer or colorectal cancer. With this trial, another frontier of cachexia management is in sight. Nonetheless, more efficacy and safety data is needed before new therapeutic indications for novel action beta-blockers can be endorsed.

 

Lainscak, M., and Laviano, A. (2016) ACT-ONE - ACTION at last on cancer cachexia by adapting a novel action beta-blocker. Journal of Cachexia, Sarcopenia and Muscle, 7: 400–402. doi: 10.1002/jcsm.12136.

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     Page 403412

David Berger, Stefan Bloechlinger, Stephan von Haehling, Wolfram Doehner, Jukka Takala, Werner J. Z'Graggen, Joerg C. Schefold

Dysfunction of respiratory muscles in critically ill patients on the intensive care unitMuscular weakness and muscle wasting may often be observed in critically ill patients on intensive care units (ICUs) and may present as failure to wean from mechanical ventilation. Importantly, mounting data demonstrate that mechanical ventilation itself may induce progressive dysfunction of the main respiratory muscle, i.e. the diaphragm. The respective condition was termed ‘ventilator-induced diaphragmatic dysfunction’ (VIDD) and should be distinguished from peripheral muscular weakness as observed in ‘ICU-acquired weakness (ICU-AW)’.

Interestingly, VIDD and ICU-AW may often be observed in critically ill patients with, e.g. severe sepsis or septic shock, and recent data demonstrate that the pathophysiology of these conditions may overlap. VIDD may mainly be characterized on a histopathological level as disuse muscular atrophy, and data demonstrate increased proteolysis and decreased protein synthesis as important underlying pathomechanisms. However, atrophy alone does not explain the observed loss of muscular force. When, e.g. isolated muscle strips are examined and force is normalized for cross-sectional fibre area, the loss is disproportionally larger than would be expected by atrophy alone. Nevertheless, although the exact molecular pathways for the induction of proteolytic systems remain incompletely understood, data now suggest that VIDD may also be triggered by mechanisms including decreased diaphragmatic blood flow or increased oxidative stress. Here we provide a concise review on the available literature on respiratory muscle weakness and VIDD in the critically ill. Potential underlying pathomechanisms will be discussed before the background of current diagnostic options. Furthermore, we will elucidate and speculate on potential novel future therapeutic avenues.

 

Berger, D., Bloechlinger, S., von Haehling, S., Doehner, W., Takala, J., Z'Graggen, W. J., and Schefold, J. C. (2016) Dysfunction of respiratory muscles in critically ill patients on the intensive care unit. Journal of Cachexia, Sarcopenia and Muscle,7: 403–412, doi: 10.1002/jcsm.12108.

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     Page 413421

Camila Lemos Pinto, Patrícia Borges Botelho, Juliana Alves Carneiro, João Felipe Mota

Impact of creatine supplementation in combination with resistance training on lean mass in the elderlyBackground
Human ageing is a process characterized by loss of muscle mass, strength, and bone mass. We aimed to examine the efficacy of low-dose creatine supplementation associated with resistance training on lean mass, strength, and bone mass in the elderly.
Methods
This was a 12-week, parallel-group, double-blind, randomized, placebo-controlled trial. The individuals were randomly allocated into one of the following groups: placebo plus resistance training (PL + RT) and creatine supplementation plus resistance training (CR + RT) . The participants were assessed at baseline and after 12 weeks. The primary outcomes were lean mass and strength, assessed by dual energy X-ray absorptiometry (DXA) and ten-repetition maximal tests (10 RM), respectively. Secondary outcomes included the lumbar spine, right and left femoral neck, both femur and whole body bone mineral density (BMD), and whole body bone mineral content (BMC), assessed by DXA.
Results
The CR + RT group had superior gains in lean mass when compared with the PL + RT group (P = 0.02). Changes in the 10 RM tests in bench press and leg press exercises, body composition, BMD, and BMC of all assessed sites did not significantly differ between the groups (P > 0.05).
Conclusions
Twelve weeks of low-dose creatine supplementation associated with resistance training resulted in increases in lean mass in the elderly.

 

Pinto, C. L., Botelho, P. B., Carneiro, J. A., and Mota, J. F. (2016) Impact of creatine supplementation in combination with resistance training on lean mass in the elderly. Journal of Cachexia, Sarcopenia and Muscle,7: 413–421, doi: 10.1002/jcsm.12094.

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     Page 422435

Nienke M. de Vries, J Bart Staal, Philip J. van der Wees, Eddy M. M. Adang, Reinier Akkermans, Marcel G. M. Olde Rikkert, Maria W. G. Nijhuis-van der Sanden

Patient-centred physical therapy is (cost-) effective in increasing physical activity and reducing frailty in older adults with mobility problems: a randomized controlled trial with 6 months follow-upBackground
Despite the well-known health benefits of physical activity, it is a great challenge to stay physically active for frail–older adults with mobility limitations. The aim of this study was to test the (cost-) effectiveness of a patient-centred physical therapy strategy (Coach2Move) in which individualized treatment (motivational interviewing, physical examination, individualized goal setting, coaching and advice on self management, and physical training) is combined to increase physical activity level and physical fitness and, thereby, to decrease the level of frailty.
Methods
A randomized controlled trial was performed in 13 physical therapy practices with measurements at 3 and 6 months. Eligible patients were aged 70 years or over and had mobility problems (i.e. difficulties with walking, moving, getting up and changing position from bed or chair to standing, or stair climbing). The primary outcome was physical activity (total and moderate intensity) in minutes per day. Secondary outcomes were as follows: frailty, walking speed and distance, mobility, and quality of life. Data were analysed using linear mixed models for repeated measurements. Healthcare costs and quality-adjusted life years (QALYs) were computed and combined using net monetary benefit (NMB) for different willingness to pay thresholds. Data on costs, QALYs, and NMBs were analysed using linear mixed models.
Results
One hundred and thirty patients participated in this study. At 6 months, the between-group difference was significant for moderate-intensity physical activity in favour of the Coach2Move group [mean difference: 17.9 min per day; 95% confidence interval (CI) 4.0 to 34.9; P = 0.012]. The between-group difference for total physical activity was 14.1 min per day (95% CI −6.6 to 34.9; P  = 0.182). Frailty decreased more in the Coach2Move group compared with usual care [mean difference: −0.03 (95% CI: −0.06 to −0.00; P = 0.027)]. Compared with usual treatment, the Coach2Move strategy resulted in cost savings (€849.8; 95% CI: 1607 to 90; P = 0.028), an improvement in QALYs, (0.02; 95% CI: 0.00 to 0.03; P = 0.03), and a higher NMB at every willingness to pay threshold.
Conclusions
Older adults with mobility problems are able to safely increase physical activity in their own environment and reduce frailty. This study emphasizes both the potential cost-effectiveness of a patient-centred approach in the frail elderly and the importance of physical activity promotion in older adults with mobility limitations.

 

 

de Vries, N. M., Staal, J. B., van der Wees, P. J., Adang, E. M. M., Akkermans, R., Olde Rikkert, M. G. M., and Nijhuis-van der Sanden, M. W. G. (2015) Patient-centred physical therapy is (cost-) effective in increasing physical activity and reducing frailty in older adults with mobility problems: a randomized controlled trial with 6 months follow-up. Journal of Cachexia, Sarcopenia and Muscle,7: 422–435, doi: 10.1002/jcsm.12091.

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     Page 436448

Mehul S. Patel, Jen Lee, Manuel Baz, Claire E. Wells, Susannah Bloch, Amy Lewis, Anna V. Donaldson, Benjamin E. Garfield, Nicholas S. Hopkinson, Amanda Natanek, William D-C Man, Dominic J. Wells, Emma H. Baker, Michael I. Polkey, Paul R. Kemp

Growth differentiation factor-15 is associated with muscle mass in chronic obstructive pulmonary disease and promotes muscle wasting in vivoBackground
Loss of muscle mass is a co-morbidity common to a range of chronic diseases including chronic obstructive pulmonary disease (COPD). Several systemic features of COPD including increased inflammatory signalling, oxidative stress, and hypoxia are known to increase the expression of growth differentiation factor-15 (GDF-15), a protein associated with muscle wasting in other diseases. We therefore hypothesized that GDF-15 may contribute to muscle wasting in COPD.
Methods
We determined the expression of GDF-15 in the serum and muscle of patients with COPD and analysed the association of GDF-15 expression with muscle mass and exercise performance. To determine whether GDF-15 had a direct effect on muscle, we also determined the effect of increased GDF-15 expression on the tibialis anterior of mice by electroporation.
Results
Growth differentiation factor-15 was increased in the circulation and muscle of COPD patients compared with controls. Circulating GDF-15 was inversely correlated with rectus femoris cross-sectional area (P < 0.001) and exercise capacity (P < 0.001) in two separate cohorts of patients but was not associated with body mass index. GDF-15 levels were associated with 8-oxo-dG in the circulation of patients consistent with a role for oxidative stress in the production of this protein. Local over-expression of GDF-15 in mice caused wasting of the tibialis anterior muscle that expressed it but not in the contralateral muscle suggesting a direct effect of GDF-15 on muscle mass (P < 0.001).
Conclusions
Together, the data suggest that GDF-15 contributes to the loss of muscle mass in COPD.

 

 

Patel, M. S., Lee, J., Baz, M., Wells, C. E., Bloch, S., Lewis, A., Donaldson, A. V., Garfield, B. E., Hopkinson, N. S., Natanek, A., Man, W. D.-C., Wells, D. J., Baker, E. H., Polkey, M. I., and Kemp, P. R. (2015) Growth differentiation factor-15 is associated with muscle mass in chronic obstructive pulmonary disease and promotes muscle wasting in vivo. Journal of Cachexia, Sarcopenia and Muscle,7: 436–448, doi: 10.1002/jcsm.12096.

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     Page 449457

Elisabetta Ferraro, Fabrizio Pin, Stefania Gorini, Laura Pontecorvo, Alberto Ferri, Vincenzo Mollace, Paola Costelli, Giuseppe Rosano

Improvement of skeletal muscle performance in ageing by the metabolic modulator TrimetazidineBackground
The loss of muscle mass (sarcopenia) and the associated reduced muscle strength are key limiting factors for elderly people's quality of life. Improving muscle performance does not necessarily correlate with increasing muscle mass. In fact, particularly in the elderly, the main explanation for muscle weakness is a reduction of muscle quality rather than a loss of muscle mass, and the main goal to be achieved is to increase muscle strength. The effectiveness of Trimetazidine (TMZ) in preventing muscle functional impairment during ageing was assessed in our laboratory.
Methods
Aged mice received TMZ or vehicle for 12 consecutive days. Muscle function was evaluated at the end of the treatment by a grip test as well as by an inverted screen test at 0, 5, 7 and 12 days of TMZ treatment. After sacrifice, muscles were stored for myofiber cross-sectional area assessment and myosin heavy chain expression evaluation by western blotting.
Results
Chronic TMZ treatment does not affect the mass of both gastrocnemius and tibialis anterior muscles, while it significantly increases muscle strength. Indeed, both latency to fall and grip force are markedly enhanced in TMZ-treated versus untreated mice. In addition, TMZ administration results in higher expression of slow myosin heavy chain isoform and increased number of small-sized myofibers.
Conclusions
We report here some data showing that the modulation of skeletal muscle metabolism by TMZ increases muscle strength in aged mice. Reprogramming metabolism might therefore be a strategy worth to be further investigated in view of improving muscle performance in the elderly.

 

Ferraro, E., Pin, F., Gorini, S., Pontecorvo, L., Ferri, A., Mollace, V., Costelli, P., and Rosano, G. (2016) Improvement of skeletal muscle performance in ageing by the metabolic modulator Trimetazidine. Journal of Cachexia, Sarcopenia and Muscle,7: 449–457, doi: 10.1002/jcsm.12097.

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     Page 458466

Iris J. G. Rutten, David P. J. van Dijk, Roy F. P. M. Kruitwagen, Regina G. H. Beets-Tan, Steven W. M. Olde Damink, Toon van Gorp

Loss of skeletal muscle during neoadjuvant chemotherapy is related to decreased survival in ovarian cancer patientsBackground
Malnutrition, weight loss, and muscle wasting (sarcopenia) are common among women with advanced ovarian cancer and have been associated with adverse clinical outcomes and survival. Our objective is to investigate overall survival (OS) related to changes in skeletal muscle (SM) for patients with advanced ovarian cancer treated with neoadjuvant chemotherapy and interval debulking.
Methods
Ovarian cancer patients (n?=?123) treated with neoadjuvant chemotherapy and interval debulking in the area of Maastricht (the Netherlands) between 2000 and 2014 were included retrospectively. Surface areas of SM and adipose tissue were defined on computed tomography at the level of the third lumbar vertebra. Low SM at baseline and SM changes during chemotherapy were compared with Kaplan Meier curves, and Cox-regression models were applied to test predictors of OS.
Results
Median OS for patients who lost SM (n?=?83) was 916?±?99?days, which was significantly different from median OS for patients who maintained or gained SM (n?=?40), which was 1431?±?470?days (P?=?0.004). Loss of SM was also a significant predictor of OS in multivariable Cox-regression analysis (hazard ratio 1.773 (95%CI: 1.018–3.088), P?=?0.043). Low baseline SM did not influence survival.
Conclusions
Patients with ovarian cancer have a worse survival when they lose SM during neoadjuvant chemotherapy. Evaluation of low SM at a specific time point is not prognostic for OS. External and prospective validation of these findings is imperative. Nutritional, pharmacological, and/or physical intervention studies are necessary to establish whether SM impairment can be prevented to prolong ovarian cancer survival.

 

Rutten, I. J. G., van Dijk, D. P. J., Kruitwagen, R. F. P. M., Beets-Tan, R. G. H., Olde Damink, S. W. M., and van Gorp, T. (2016) Loss of skeletal muscle during neoadjuvant chemotherapy is related to decreased survival in ovarian cancer patients. Journal of Cachexia, Sarcopenia and Muscle,7: 458–466, doi: 10.1002/jcsm.12107.

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     Page 467482

Lorena Lerner, Julie Tao, Qing Liu, Richard Nicoletti, Bin Feng, Brian Krieger, Elizabeth Mazsa, Zakir Siddiquee, Ruoji Wang, Lucia Huang, Luhua Shen, Jie Lin, Antonio Vigano, M. Isabel Chiu, Zhigang Wen1, William Winston, Solly Weiler, Jeno Gyuris

MAP3K11/GDF15 axis is a critical driver of cancer cachexiaBackground
Cancer associated cachexia affects the majority of cancer patients during the course of the disease and thought to be directly responsible for about a quarter of all cancer deaths. Current evidence suggests that a pro-inflammatory state may be associated with this syndrome although the molecular mechanisms responsible for the development of cachexia are poorly understood. The purpose of this work was the identification of key drivers of cancer cachexia that could provide a potential point of intervention for the treatment and/or prevention of this syndrome.
Methods
Genetically engineered and xenograft tumour models were used to dissect the molecular mechanisms driving cancer cachexia. Cytokine profiling from the plasma of cachectic and non-cachectic cancer patients and mouse models was utilized to correlate circulating cytokine levels with the cachexia phenotype.
Results
Utilizing engineered tumour models we identified MAP3K11/GDF15 pathway activation as a potent inducer of cancer cachexia. Increased expression and high circulating levels of GDF15 acted as a key mediator of this process. In animal models, tumour-produced GDF15 was sufficient to trigger the cachexia phenotype. Elevated GDF15 circulating levels correlated with the onset and progression of cachexia in animal models and in patients with cancer. Inhibition of GDF15 biological activity with a specific antibody reversed body weight loss and restored muscle and fat tissue mass in several cachectic animal models regardless of their complex secreted cytokine profile.
Conclusions
The combination of correlative observations, gain of function, and loss of function experiments validated GDF15 as a key driver of cancer cachexia and as a potential therapeutic target for the treatment and/or prevention of this syndrome.

 

Lerner, L., Tao, J., Liu, Q., Nicoletti, R., Feng, B., Krieger, B., Mazsa, E., Siddiquee, Z., Wang, R., Huang, L., Shen, L., Lin, J., Vigano, A., Chiu, M. I., Weng, Z., Winston, W., Weiler, S., and Gyuris, J. (2015) MAP3K11/GDF15 axis is a critical driver of cancer cachexia. Journal of Cachexia, Sarcopenia and Muscle,7: 467–482, doi: 10.1002/jcsm.12077.

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     Page 467482

Kamil Kowalski, Rafał Archacki, Karolina Archacka, Władysława Stremińska, Anna Paciorek, Magdalena Gołąbek, Maria A. Ciemerych, Edyta Brzoska

Stromal derived factor-1 and granulocyte-colony stimulating factor treatment improves regeneration of Pax7−/− mice skeletal musclesBackground
The skeletal muscle has the ability to regenerate after injury. This process is mediated mainly by the muscle specific stem cells, that is, satellite cells. In case of extensive damage or under pathological conditions, such as muscular dystrophy, the process of muscle reconstruction does not occur properly. The aim of our study was to test whether mobilized stem cells, other than satellite cells, could participate in skeletal muscle reconstruction.
Methods
Experiments were performed on wild-type mice and mice lacking the functional Pax7 gene, that is, characterized by the very limited satellite cell population. Gastrocnemius mice muscles were injured by cardiotoxin injection, and then the animals were treated by stromal derived factor-1 (Sdf-1) with or without granulocyte-colony stimulating factor (G-CSF) for 4 days. The muscles were subjected to thorough assessment of the tissue regeneration process using histological and in vitro methods, as well as evaluation of myogenic factors' expression at the transcript and protein levels.
Results
Stromal derived factor-1 alone and Sdf-1 in combination with G-CSF significantly improved the regeneration of Pax7−/− skeletal muscles. The Sdf-1 and G-CSF treatment caused an increase in the number of mononucleated cells associated with muscle fibres. Further analysis showed that Sdf-1 and G-CSF treatment led to the rise in the number of CD34+ and Cxcr4+ cells and expression of Cxcr7.
Conclusions
Stromal derived factor-1 and G-CSF stimulated regeneration of the skeletal muscles deficient in satellite cells. We suggest that mobilized CD34+, Cxcr4+, and Cxcr7+ cells can efficiently participate in the skeletal muscle reconstruction and compensate for the lack of satellite cells.

 

Kowalski, K., Archacki, R., Archacka, K., Stremińska, W., Paciorek, A., Gołąbek, M., Ciemerych, M. A., and Brzoska, E. (2015) Stromal derived factor-1 and granulocyte-colony stimulating factor treatment improves regeneration of Pax7−/− mice skeletal muscles. Journal of Cachexia, Sarcopenia and Muscle,7: 483–496, doi: 10.1002/jcsm.12092.

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     Page 497498

Masaaki Konishi, Junichi Ishida, Masakazu Saitoh, Jochen Springer

Clinical perspective for wasting in diaphragm, an ever-trained muscleno abstract

 

Konishi, M., Ishida, J., Saitoh, M., and Springer, J. (2016) Clinical perspective for wasting in diaphragm, an ever-trained muscle. Journal of Cachexia, Sarcopenia and Muscle,7: 497–498, ddoi: 10.1002/jcsm.12125.

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     Page 499500

Todd M. Manini, Brian C. Clark

Letter to the editor: results from a Web-based survey to identify dynapenia screening tools and risk factorsno abstract

 

Manini, T. M., and Clark, B. C. (2016) Letter to the editor: results from a Web-based survey to identify dynapenia screening tools and risk factors. Journal of Cachexia, Sarcopenia and Muscle, 7: 499–500. doi: 10.1002/jcsm.12128.

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     Page 501502

Addendum to ‘Abstracts of the 8th International Conference on Cachexia, Sarcopenia and Muscle Wasting, Paris, France, 4–6 December 2015’no abstract

 

 

Scherbakov, N. (2016) Addendum to ‘Abstracts of the 8th International Conference on Cachexia, Sarcopenia and Muscle Wasting, Paris, France, 4–6 December 2015’. Journal of Cachexia, Sarcopenia and Muscle, 7: 501–502. doi: 10.1002/jcsm.12141.

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     Page 503

Corrigendum to: Prevalence of sarcopenia among community-dwelling elderly of a medium-sized South American city: results of the COMO VAI? studyno abstract

 

 

(2016), Corrigendum to: Prevalence of sarcopenia among community-dwelling elderly of a medium-sized South American city: results of the COMO VAI? study. Journal of Cachexia, Sarcopenia and Muscle, 7: 503. doi: 10.1002/jcsm.12143

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Number 5 / September 2016

 

     Page 507–509

Stephan von Haehling, Markus S. Anker, Stefan D. Anker

Prevalence and clinical impact of cachexia in chronic illness in Europe, USA, and Japan: facts and numbers update 2016Cachexia is a serious clinical consequence of almost all chronic diseases when reaching advanced stages. Its prevalence ranges from 5–15% in end-stage chronic heart failure to 50–80% in advanced malignant cancer. Cachexia is also frequently occurring in patients with chronic kidney disease, chronic obstructive pulmonary disease (COPD) or neurological diseases, and rheumatoid arthritis. Mortality rates of patients with cachexia range from 15–25% per year in severe COPD through 20–40% per year in patients with chronic heart failure or chronic kidney disease to 20–80% in cancer cachexia. In the industrialized world (North America, Europe, and Japan) where epidemiological data are to some degree available, the overall prevalence of cachexia (due to any disease and not necessarily associated with hospital admission) is growing with the growth of the chronic illness prevalence, and it currently affects around 0.5–1.0% of the population, i.e. around 6–12 million people. From this, one can estimate that 1.5–2 million deaths are occurring in patients with cachexia per year. It is also a very significant health problem in other parts of the globe, but epidemiological data are scarce. The multifactorial nature of cachexia is now much better understood, and particularly, the role of inflammatory mediators and the imbalance of anabolism and catabolism are considered important therapeutic targets. Several approaches to develop cachexia and muscle wasting treatments have failed to be successful in phase III clinical trials, but new approaches are in development. Given the high prevalence and very high mortality associated with cachexia, advances are urgently needed for patients worldwide.

 

von Haehling, S., Anker, M. S., and Anker, S. D. (2016) Prevalence and clinical impact of cachexia in chronic illness in Europe, USA, and Japan: facts and numbers update 2016. Journal of Cachexia, Sarcopenia and Muscle, 7: 507–509. doi: 10.1002/jcsm.12167.

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     Page 510–511

Alessandro Laviano, Alessio Molfino

Cachexia: looking yet not seeingno abstract

 

Laviano, A., and Molfino, A. (2016) Cachexia: looking yet not seeing. Journal of Cachexia, Sarcopenia and Muscle, 7: 510–511. doi: 10.1002/jcsm.12120.

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     Page 512–514.

Stefan D. Anker, John E. Morley, Stephan von Haehling

Welcome to the ICD-10 code for sarcopeniaThe new ICD-10-CM (M62.84) code for sarcopenia represents a major step forward in recognizing sarcopenia as a disease. This should lead to an increase in availability of diagnostic tools and the enthusiasm for pharmacological companies to develop drugs for sarcopenia.

 

Anker, S. D., Morley, J. E., and von Haehling, S. (2016) Welcome to the ICD-10 code for sarcopenia. Journal of Cachexia, Sarcopenia and Muscle, 7: 512–514. doi: 10.1002/jcsm.12147.

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     Page 515–519

Masaaki Konishi, Junichi Ishida, Jochen Springer, Stefan D. Anker, Stephan von Haehling

Cachexia research in Japan: facts and numbers on prevalence, incidence and clinical impactBackground
Sarcopenia is known to be related to an increased risk of chemotherapy toxicity and to a poor prognosis in patients with malignancy. We assessed the prognostic role of sarcopenia in patients with diffuse large B-cell lymphoma (DLBCL).
Methods
In total, 187 consecutive patients with DLBCL treated with induction rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisolone (R-CHOP) immunochemotherapy were reviewed. Sarcopenia was defined as the lowest sex-specific quartile of the skeletal muscle index, calculated by dividing the pectoralis muscle area by the height. Clinical outcomes were compared between the sarcopenic and non-sarcopenic groups. A nomogram was constructed from the Cox regression model for overall survival (OS).
Results
Treatment-related mortality (21.7 vs. 5.0%, P = 0.002) and early discontinuation of treatment (32.6 vs. 14.9%, P = 0.008) were more common in the sarcopenic group than in the non-sarcopenic group. The 5 year progression-free survival (PFS) rates were 35.3% in the sarcopenic group and 65.8% in the non-sarcopenic group (P < 0.001). The 5 year OS rates were 37.3% in the sarcopenic group and 68.1% in the non-sarcopenic group (P < 0.001). Sarcopenia and the five variables of the International Prognostic Index (IPI) were independent prognostic factors in a multivariate analysis for PFS and OS and were used to construct the nomogram. The calibration plot showed good agreement between the nomogram predictions and actual observations. The c index of the nomogram (0.80) was higher than those of other prognostic indices (IPI, 0.77, P = 0.009; revised-IPI, 0.74, P < 0.001; National Comprehensive Cancer Network-IPI, 0.77, P = 0.062).
Conclusions
Sarcopenia is associated with intolerance to standard R-CHOP chemotherapy as well as a poor prognosis. Moreover, sarcopenia itself can be included in prognostic models in DLBCL.

 

Konishi, M., Ishida, J., Springer, J., Anker, S. D., and von Haehling, S. (2016) Cachexia research in Japan: facts and numbers on prevalence, incidence and clinical impact. Journal of Cachexia, Sarcopenia and Muscle, 7: 515–519. doi: 10.1002/jcsm.12117.

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     Page 520–526

Bronwen Connolly, Lisa Salisbury, Brenda O'Neill, Louise Geneen, Abdel Douiri, Michael P. W. Grocott, Nicholas Hart, Timothy S. Walsh, Bronagh Blackwood

Exercise rehabilitation following intensive care unit discharge for recovery from critical illness: executive summary of a Cochrane Collaboration systematic reviewSkeletal muscle wasting and weakness are major complications of critical illness and underlie the profound physical and functional impairments experienced by survivors after discharge from the intensive care unit (ICU). Exercise-based rehabilitation has been shown to be beneficial when delivered during ICU admission. This review aimed to determine the effectiveness of exercise rehabilitation initiated after ICU discharge on primary outcomes of functional exercise capacity and health-related quality of life. We sought randomized controlled trials, quasi-randomized controlled trials, and controlled clinical trials comparing an exercise intervention commenced after ICU discharge vs. any other intervention or a control or ‘usual care’ programme in adult survivors of critical illness. Cochrane Central Register of Controlled Trials, Medical Literature Analysis and Retrieval System Online (MEDLINE), Excerpta Medica Database, and Cumulative Index to Nursing and Allied Health Literature databases were searched up to February 2015. Dual, independent screening of results, data extraction, and quality appraisal were performed. We included six trials involving 483 patients. Overall quality of evidence for both outcomes was very low. All studies evaluated functional exercise capacity, with three reporting positive effects in favour of the intervention. Only two studies evaluated health-related quality of life and neither reported differences between intervention and control groups. Meta-analyses of data were precluded due to variation in study design, types of interventions, and selection and reporting of outcome measurements. We were unable to determine an overall effect on functional exercise capacity or health-related quality of life of interventions initiated after ICU discharge for survivors of critical illness. Findings from ongoing studies are awaited. Future studies need to address methodological aspects of study design and conduct to enhance rigour, quality, and synthesis.

 

 

Connolly, B., Salisbury, L., O'Neill, B., Geneen, L., Douiri, A., Grocott, M. P. W., Hart, N., Walsh, T. S., and Blackwood, B. (2016) Exercise rehabilitation following intensive care unit discharge for recovery from critical illness: executive summary of a Cochrane Collaboration systematic review. Journal of Cachexia, Sarcopenia and Muscle, 7: 520–526. doi: 10.1002/jcsm.12146.

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     Page 527–534

Koji Amano, Isseki Maeda, Tatsuya Morita, Yoshiro Okajima, Takashi Hama, Maho Aoyama, Yoshiyuki Kizawa, Satoru Tsuneto, Yasuo Shima, Mitsunori Miyashita

Eating-related distress and need for nutritional support of families of advanced cancer patients: a nationwide survey of bereaved family membersBackground
A number of advanced cancer patients are suffering from physical and psychosocial burdens because of cancer cachexia, and these burdens also greatly impact on their family members and relationships between patients and family members. It is necessary to consider the psychosocial impact of cancer cachexia on family members of advanced cancer patients.
Methods
A cross-sectional anonymous nationwide survey was conducted involving 925 bereaved family members of cancer patients who had been admitted to 133 inpatient hospices throughout Japan.
Results
A total of 702 bereaved family members returned the questionnaires (response rate, 75.9%). Concerning eating-related distress, ‘I served what the patient wanted without consideration of calories and nutritional composition’ was highest (75.1%), and ‘I tried making many kinds of meals for the patient’ and ‘I was concerned about planning meals for the patient every day’ followed (63.0% and 59.4%, respectively). The top 5 of the 19 items were categorized as ‘fighting back’. Need for nutritional support was high (72.2%), and need for explanations about the reasons for anorexia and weight loss of patients was moderate (41.4%). Explanatory factor analysis of eating-related distress identified the following four domains: (factor 1) feeling that family members forced the patient to eat to avoid death, (factor 2) feeling that family members made great efforts to help the patient eat, (factor 3) feeling that eating was a cause of conflicts between the patient and family members, and (factor 4) feeling that correct information was insufficient. Results of multiple logistic regression analysis showed that spouse, fair/poor mental status, factors 1, and 4 were identified as independent determinants of major depression {odds ratio [OR] 3.27 [95% confidence interval (CI) 1.24–8.60], P = 0.02; OR 4.50 [95% CI 2.46–8.25], P < 0.001; OR 2.51 [95% CI 1.16–5.45], P = 0.02; OR 2.33 [95% CI 1.13–4.80], P = 0.02, respectively}.
Conclusions
A number of family members of advanced cancer patients experienced high levels of eating-related distress and had a need for nutritional support.

 

 

Amano, K., Maeda, I., Morita, T., Okajima, Y., Hama, T., Aoyama, M., Kizawa, Y., Tsuneto, S., Shima, Y., and Miyashita, M. (2016) Eating-related distress and need for nutritional support of families of advanced cancer patients: a nationwide survey of bereaved family members. Journal of Cachexia, Sarcopenia and Muscle, 7: 527–534. doi: 10.1002/jcsm.12102.

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     Page 535–546

Darryl P. Leong, Koon K. Teo1, Sumathy Rangarajan, V. Raman Kutty, Fernando Lanas, Chen Hui, Xiang Quanyong, Qian Zhenzhen, Tang Jinhua, Ismail Noorhassim,Khalid F AlHabib, Sarah J. Moss, Annika Rosengren, Ayse Arzu Akalin, Omar Rahman, Jephat Chifamba, Andrés Orlandini, Rajesh Kumar, Karen Yeates, Rajeev Gupta, Afzalhussein Yusufali, Antonio Dans, Álvaro Avezum, Patricio Lopez-Jaramillo, Paul Poirier, Hosein Heidari, Katarzyna Zatonska, Romaina Iqbal, Rasha Khatib, Salim Yusuf

Reference ranges of handgrip strength from 125,462 healthy adults in 21 countries: a prospective urban rural epidemiologic (PURE) studyBackground
The measurement of handgrip strength (HGS) has prognostic value with respect to all-cause mortality, cardiovascular mortality and cardiovascular disease, and is an important part of the evaluation of frailty. Published reference ranges for HGS are mostly derived from Caucasian populations in high-income countries. There is a paucity of information on normative HGS values in non-Caucasian populations from low- or middle-income countries. The objective of this study was to develop reference HGS ranges for healthy adults from a broad range of ethnicities and socioeconomically diverse geographic regions.
Methods
HGS was measured using a Jamar dynamometer in 125,462 healthy adults aged 35-70 years from 21 countries in the Prospective Urban Rural Epidemiology (PURE) study.
Results
HGS values differed among individuals from different geographic regions. HGS values were highest among those from Europe/North America, lowest among those from South Asia, South East Asia and Africa, and intermediate among those from China, South America, and the Middle East. Reference ranges stratified by geographic region, age, and sex are presented. These ranges varied from a median (25th–75th percentile) 50 kg (43–56 kg) in men <40 years from Europe/North America to 18 kg (14–20 kg) in women >60 years from South East Asia. Reference ranges by ethnicity and body-mass index are also reported.
Conclusions
Individual HGS measurements should be interpreted using region/ethnic-specific reference ranges.

 

Leong, D. P., Teo, K. K., Rangarajan, S., Kutty, V. R., Lanas, F., Hui, C., Quanyong, X., Zhenzhen, Q., Jinhua, T., Noorhassim, I., AlHabib, K. F., Moss, S. J., Rosengren, A., Akalin, A. A., Rahman, O., Chifamba, J., Orlandini, A., Kumar, R., Yeates, K., Gupta, R., Yusufali, A., Dans, A., Avezum, Á., Lopez-Jaramillo, P., Poirier, P., Heidari, H., Zatonska, K., Iqbal, R., Khatib, R., and Yusuf, S. (2016) Reference ranges of handgrip strength from 125,462 healthy adults in 21 countries: a prospective urban rural epidemiologic (PURE) study. Journal of Cachexia, Sarcopenia and Muscle, 7: 535–546. doi: 10.1002/jcsm.12112.

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     Page 547–554

Joshua P Nederveen, Sophie Joanisse, Tim Snijders, Victoria Ivankovic, Steven K. Baker, Stuart M. Phillips, Gianni Parise

Skeletal muscle satellite cells are located at a closer proximity to capillaries in healthy young compared with older menBackground
Skeletal muscle satellite cells (SC) are instrumental in maintenance of muscle fibres, the adaptive responses to exercise, and there is an age-related decline in SC. A spatial relationship exists between SC and muscle fibre capillaries. In the present study, we aimed to investigate whether chronologic age has an impact on the spatial relationship between SC and muscle fibre capillaries. Secondly, we determined whether this spatial relationship changes in response to a single session of resistance exercise.
Methods
Muscle biopsies were obtained from the vastus lateralis of previously untrained young men (YM, 24 ± 3 years; n = 23) and older men (OM, 67 ± 4 years; n = 22) at rest. A subset of YM (n  = 9) performed a single bout of resistance exercise, where additional muscle biopsies taken at 24 and 72 h post-exercise recovery. Skeletal muscle fibre capillarization, SC content, and activation status were assessed using immunofluorescent microscopy of muscle cross sections.
Results
Type II muscle fibre SC and capillary content was significantly lower in the OM compared with YM (P  < 0.05). Furthermore, type II muscle fibre SC were located at a greater distance from the nearest capillary in OM compared with YM (21.6 ± 1.3 vs. 17.0 ± 0.8 µm, respectively; P < 0.05). In response to a single bout of exercise, we observed a significant increase in SC number and activation status (P < 0.05). In addition, activated vs. quiescent SC were situated closer (P < 0.05) to capillaries.
Conclusions
We demonstrate that there is a greater distance between capillaries and type II fibre-associated SC in OM as compared with YM. Furthermore, quiescent SC are located significantly further away from capillaries than active SC after single bout of exercise. Our data have implications for how muscle adapts to exercise and how aging may affect such adaptations.

 

Nederveen, J. P., Joanisse, S., Snijders, T., Ivankovic, V., Baker, S. K., Phillips, S. M., and Parise, G. (2016) Skeletal muscle satellite cells are located at a closer proximity to capillaries in healthy young compared with older men. Journal of Cachexia, Sarcopenia and Muscle, 7: 547–554. doi: 10.1002/jcsm.12105.

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     Page 555–566

Vincenzo Musolino, Sandra Palus, Anika Tschirner, Cathleen Drescher, Micaela Gliozzi, Cristina Carresi, Cristiana Vitale, Carolina Muscoli, Wolfram Doehner, Stephan von Haehling, Stefan D. Anker, Vincenzo Mollace, Jochen Springer

Megestrol acetate improves cardiac function in a model of cancer cachexia-induced cardiomyopathy by autophagic modulationBackground
Cachexia is a complex metabolic syndrome associated with cancer. One of the features of cachexia is the loss of muscle mass, characterized by an imbalance between protein synthesis and protein degradation. Muscle atrophy is caused by the hyperactivation of some of the main cellular catabolic pathways, including autophagy. Cachexia also affects the cardiac muscle. As a consequence of the atrophy of the heart, cardiac function is impaired and mortality is increased. Anti-cachectic therapy in patients with cancer cachexia is so far limited to nutritional support and anabolic steroids. The use of the appetite stimulant megestrol acetate (MA) has been discussed as a treatment for cachexia.
Methods
In this study the effects of MA were tested in cachectic tumour-bearing rats (Yoshida AH-130 ascites hepatoma). Rats were treated daily with 100 mg/kg of MA or placebo starting one day after tumour inoculation, and for a period of 16 days. Body weight and body composition were assessed at baseline and at the end of the study. Cardiac function was analysed by echocardiography at baseline and at day 11. Locomotor activity and food intake were assessed before tumour inoculation and at day 11. Autophagic markers were assessed in gastrocnemius muscle and heart by western blot analysis.
Results
Treatment with 100 mg/kg/day MA significantly attenuated the loss of body weight (−9 ± 12%, P < 0.05) and the wasting of lean and fat mass (−7.0 ± 6% and −22.4 ± 3 %, P < 0.001 and P < 0.05, respectively). Administration of 100 mg/kg/day MA significantly protected the heart from general atrophy (633.8 ± 30 mg vs. placebo 474 ± 13 mg, P < 0.001). Tumour-bearing rats displayed cardiac dysfunction, as indicated by the significant impairment of the left ventricular ejection fraction, the left ventricular fractional shortening, the stroke volume, the end dyastolic volume, and the end systolic volume. In contrast, MA significantly improved left ventricular ejection fraction, left ventricular fractional shortening, and left ventricular end systolic volume. Western blotting analysis showed an upregulation of the autophagic pathway in the gastrocnemius and hearts of the placebo-treated tumour-bearing rats. Treatment with MA, however, was able to modulate the autophagic markers (e.g. Beclin-1, p62, TRAF6, and LC3) in the gastrocnemius and in the hearts of tumour-bearing rats. Most importantly, 100 mg/kg/day MA reduced mortality [hazard ratio (HR): 0.44; 95%CI: 0.20–1.00; P = 0.0486].
Conclusions
Megestrol acetate improved survival and reduced wasting through a marked downregulation of autophagy, occurring in both skeletal and heart muscle, the latter effect leading to a significant improvement of cardiac function. Our data suggest that MA might represent a valuable strategy to counteract the development of cancer cachexia-induced cardiomyopathy.

 

Musolino, V., Palus, S., Tschirner, A., Drescher, C., Gliozzi, M., Carresi, C., Vitale, C., Muscoli, C., Doehner, W., von Haehling, S., Anker, S. D., Mollace, V., and Springer, J. (2016) Megestrol acetate improves cardiac function in a model of cancer cachexia-induced cardiomyopathy by autophagic modulation. Journal of Cachexia, Sarcopenia and Muscle, 7: 555–566. doi: 10.1002/jcsm.12116.

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     Page 567–576

Se-Il Go, Mi Jung Park, Haa-Na Song, Hoon-Gu Kim, Myoung Hee Kang, Hyang Rae Lee, Yire Kim, Rock Bum Kim, Soon Il Lee, Gyeong-Won Lee

Prognostic impact of sarcopenia in patients with diffuse large B-cell lymphoma treated with rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone
Background
Sarcopenia is known to be related to an increased risk of chemotherapy toxicity and to a poor prognosis in patients with malignancy. We assessed the prognostic role of sarcopenia in patients with diffuse large B-cell lymphoma (DLBCL).
Methods
In total, 187 consecutive patients with DLBCL treated with induction rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisolone (R-CHOP) immunochemotherapy were reviewed. Sarcopenia was defined as the lowest sex-specific quartile of the skeletal muscle index, calculated by dividing the pectoralis muscle area by the height. Clinical outcomes were compared between the sarcopenic and non-sarcopenic groups. A nomogram was constructed from the Cox regression model for overall survival (OS).
Results
Treatment-related mortality (21.7 vs. 5.0%, P = 0.002) and early discontinuation of treatment (32.6 vs. 14.9%, P = 0.008) were more common in the sarcopenic group than in the non-sarcopenic group. The 5 year progression-free survival (PFS) rates were 35.3% in the sarcopenic group and 65.8% in the non-sarcopenic group (P < 0.001). The 5 year OS rates were 37.3% in the sarcopenic group and 68.1% in the non-sarcopenic group (P < 0.001). Sarcopenia and the five variables of the International Prognostic Index (IPI) were independent prognostic factors in a multivariate analysis for PFS and OS and were used to construct the nomogram. The calibration plot showed good agreement between the nomogram predictions and actual observations. The c index of the nomogram (0.80) was higher than those of other prognostic indices (IPI, 0.77, P = 0.009; revised-IPI, 0.74, P < 0.001; National Comprehensive Cancer Network-IPI, 0.77, P = 0.062).
Conclusions
Sarcopenia is associated with intolerance to standard R-CHOP chemotherapy as well as a poor prognosis. Moreover, sarcopenia itself can be included in prognostic models in DLBCL.

 

Go, S. -I., Park, M. J., Song, H. -N., Kim, H. -G., Kang, M. H., Lee, H. R., Kim, Y., Kim, R. B., Lee, S. I., and Lee, G. -W. (2016) Prognostic impact of sarcopenia in patients with diffuse large B-cell lymphoma treated with rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone. Journal of Cachexia, Sarcopenia and Muscle, 7: 567–576. doi: 10.1002/jcsm.12115.

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     Page 577–586

Aline Tatiane Toneto, Luiz Alberto Ferreira Ramos, Emilianne Miguel Salomão, Rebeka Tomasin, Miguel Arcanjo Aereas, Maria Cristina Cintra Gomes-Marcondes

Nutritional leucine supplementation attenuates cardiac failure in tumour-bearing cachectic animalsBackground
The condition known as cachexia presents in most patients with malignant tumours, leading to a poor quality of life and premature death. Although the cancer-cachexia state primarily affects skeletal muscle, possible damage in the cardiac muscle remains to be better characterized and elucidated. Leucine, which is a branched chain amino acid, is very useful for preserving lean body mass. Thus, this amino acid has been studied as a coadjuvant therapy in cachectic cancer patients, but whether this treatment attenuates the effects of cachexia and improves cardiac function remains poorly understood. Therefore, using an experimental cancer-cachexia model, we evaluated whether leucine supplementation ameliorates cachexia in the heart.
Methods
Male Wistar rats were fed either a leucine-rich or a normoprotein diet and implanted or not with subcutaneous Walker-256 carcinoma. During the cachectic stage (approximately 21?days after tumour implantation), when the tumour mass was greater than 10% of body weight, the rats were subjected to an electrocardiogram analysis to evaluate the heart rate, QT-c, and T wave amplitude. The myocardial tissues were assayed for proteolytic enzymes (chymotrypsin, alkaline phosphatase, cathepsin, and calpain), cardiomyopathy biomarkers (myeloperoxidase, tissue inhibitor of metalloproteinases, and total plasminogen activator inhibitor 1), and caspase-8, -9, -3, and -7 activity.
Results
Both groups of tumour-bearing rats, especially the untreated group, had electrocardiography alterations that were suggestive of ischemia, dilated cardiomyopathy, and sudden death risk. Additionally, the rats in the untreated tumour-bearing group but not their leucine-supplemented littermates exhibited remarkable increases in chymotrypsin activity and all three heart failure biomarkers analysed, including an increase in caspase-3 and -7 activity.
Conclusions
Our data suggest that a leucine-rich diet could modulate heart damage, cardiomyocyte proteolysis, and apoptosis driven by cancer-cachexia. Further studies must be conducted to elucidate leucine's mechanisms of action, which potentially includes the modulation of the heart's inflammatory process.

 

Toneto, A. T., Ferreira Ramos, L. A., Salomão, E. M., Tomasin, R., Aereas, M. A., and Gomes-Marcondes, M. C. C. (2016) Nutritional leucine supplementation attenuates cardiac failure in tumour-bearing cachectic animals. Journal of Cachexia, Sarcopenia and Muscle, 7: 577–586. doi: 10.1002/jcsm.12100.

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     Page 587–603

Christiane Deval, Frédéric Capel, Brigitte Laillet, Cécile Polge, Daniel Béchet, Daniel Taillandier, Didier Attaix, Lydie Combaret

Docosahexaenoic acid-supplementation prior to fasting prevents muscle atrophy in miceBackground
Muscle wasting prevails in numerous diseases (e.g. diabetes, cardiovascular and kidney diseases, COPD,…) and increases healthcare costs. A major clinical issue is to devise new strategies preventing muscle wasting. We hypothesized that 8-week docosahexaenoic acid (DHA) supplementation prior to fasting may preserve muscle mass in vivo.
Methods
Six-week-old C57BL/6 mice were fed a DHA-enriched or a control diet for 8?weeks and then fasted for 48?h.
Results
Feeding mice a DHA-enriched diet prior to fasting elevated muscle glycogen contents, reduced muscle wasting, blocked the 55% decrease in Akt phosphorylation, and reduced by 30–40% the activation of AMPK, ubiquitination, or autophagy. The DHA-enriched diet fully abolished the fasting induced-messenger RNA (mRNA) over-expression of the endocannabinoid receptor-1. Finally, DHA prevented or modulated the fasting-dependent increase in muscle mRNA levels for Rab18, PLD1, and perilipins, which determine the formation and fate of lipid droplets, in parallel with muscle sparing.
Conclusions
These data suggest that 8-week DHA supplementation increased energy stores that can be efficiently mobilized, and thus preserved muscle mass in response to fasting through the regulation of Akt- and AMPK-dependent signalling pathways for reducing proteolysis activation. Whether a nutritional strategy aiming at increasing energy status may shorten recovery periods in clinical settings remains to be tested.

 

Deval, C., Capel, F., Laillet, B., Polge, C., Béchet, D., Taillandier, D., Attaix, D., and Combaret, L. (2016) Docosahexaenoic acid-supplementation prior to fasting prevents muscle atrophy in mice. Journal of Cachexia, Sarcopenia and Muscle, 7: 587–603. doi: 10.1002/jcsm.12103.

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     Page 604–614

Roland W. J. Hangelbroek, Parastoo Fazelzadeh, Michael Tieland, Mark V. Boekschoten, Guido J. E. J. Hooiveld, John P. M. van Duynhoven, James A. Timmons, Lex B. Verdijk, Lisette C. P. G. M. de Groot, Luc J. C. van Loon, Michael Müller

Expression of protocadherin gamma in skeletal muscle tissue is associated with age and muscle weaknessBackground
The skeletal muscle system plays an important role in the independence of older adults. In this study we examine differences in the skeletal muscle transcriptome between healthy young and older subjects and (pre-)frail older adults. Additionally, we examine the effect of resistance-type exercise training on the muscle transcriptome in healthy older subjects and (pre-)frail older adults.
Methods
Baseline transcriptome profiles were measured in muscle biopsies collected from 53 young, 73 healthy older subjects, and 61 frail older subjects. Follow-up samples from these frail older subjects (31 samples) and healthy older subjects (41 samples) were collected after 6 months of progressive resistance-type exercise training. Frail older subjects trained twice per week and the healthy older subjects trained three times per week.
Results
At baseline genes related to mitochondrial function and energy metabolism were differentially expressed between older and young subjects, as well as between healthy and frail older subjects. Three hundred seven genes were differentially expressed after training in both groups. Training affected expression levels of genes related to extracellular matrix, glucose metabolism ,and vascularization. Expression of genes that were modulated by exercise training was indicative of muscle strength at baseline. Genes that strongly correlated with strength belonged to the protocadherin gamma gene cluster (r = −0.73).
Conclusion
Our data suggest significant remaining plasticity of ageing skeletal muscle to adapt to resistance-type exercise training. Some age-related changes in skeletal muscle gene expression appear to be partially reversed by prolonged resistance-type exercise training. The protocadherin gamma gene cluster may be related to muscle denervation and re-innervation in ageing muscle.

 

Hangelbroek, R. W. J., Fazelzadeh, P., Tieland, M., Boekschoten, M. V., Hooiveld, G. J. E. J., van Duynhoven, J. P. M., Timmons, J. A., Verdijk, L. B., de Groot, L. C. P. G. M., van Loon, L. J. C., and Müller, M. (2016) Expression of protocadherin gamma in skeletal muscle tissue is associated with age and muscle weakness. Journal of Cachexia, Sarcopenia and Muscle, 7: 604–614. doi: 10.1002/jcsm.12099.

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     Page 615–625

Edson Alves de Lima Junior, Alex Shimura Yamashita, Gustavo Duarte Pimentel, Luís G. O. De Sousa, Ronaldo Vagner T Santos, Cinara Ludvig Gonçalves, Emilio Luiz Streck, Fábio Santos de Lira, Jose Cesar Rosa Neto

Doxorubicin caused severe hyperglycaemia and insulin resistance, mediated by inhibition in AMPk signalling in skeletal muscleBackground
Cancer is considered the second leading cause of death in the world, and for the treatment of this disease, pharmacological intervention strategies are frequently based on chemotherapy. Doxorubicin (DOX) is one of the most widely used chemotherapeutic agents in clinical practice for treating a number of solid tumours. The treatment with DOX mimics some effects of cancer cachexia, such as anorexia, asthenia, decreases in fat and skeletal muscle mass and fatigue. We observed that treatment with DOX increased the systemic insulin resistance and caused a massive increase in glucose levels in serum. Skeletal muscle is a major tissue responsible for glucose uptake, and the positive role of AMPk protein (AMP-activated protein kinase) in GLUT-4 (Glucose Transporter type 4) translocation, is well established. With this, our aim was to assess the insulin sensitivity after treatment with DOX and involvement of AMPk signalling in skeletal muscle in this process.
Methods
We used Wistar rats which received a single dose of doxorubicin (DOX group) or saline (CT group) intraperitoneally at a dose of 15?mg/kg b.w. The expression of proteins involved in insulin sensitivity, glucose uptake, inflammation, and activity of electron transport chain was assessed in extensor digitorum longus muscle, as well as the histological evaluation. In vitro assays were performed in L6 myocytes to assess glucose uptake after treatment with DOX. Agonist of AMPk [5-aminoimidazole-4-carboxamide (AICAR)] and the antioxidant n-acetyl cysteine were used in L6 cells to evaluate its effect on glucose uptake and cell viability.
Results
The animals showed a significant insulin resistance, hyperglycaemia, and hyperinsulinemia. A decrease in the expression of AMKP and GLUT-4 was observed in the extensor digitorum longus muscle. Also in L6 cells, DOX leads to a decrease in glucose uptake, which is reversed with AICAR.
Conclusions
DOX leads to conditions similar to cachexia, with severe glucose intolerance both in vivo and in vitro. The decrease of AMPk activity of the protein is modulated negatively with DOX, and treatment with agonist of AMPk (AICAR) has proved to be a possible therapeutic target, which is able to recover glucose sensitivity in skeletal muscle.

 

de Lima Junior, E. A., Yamashita, A. S., Pimentel, G. D., De Sousa, L. G. O., Santos, R. V. T., Gonçalves, C. L., Streck, E. L., de Lira, F. S., and Rosa Neto, J. C. (2016) Doxorubicin caused severe hyperglycaemia and insulin resistance, mediated by inhibition in AMPk signalling in skeletal muscle. Journal of Cachexia, Sarcopenia and Muscle, 7: 615–625. doi: 10.1002/jcsm.12104.

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Abstracts of the 9th International Conference on Cachexia, Sarcopenia and Muscle Wasting, Berlin, Germany, 10–11 December 2016 (part 1) (pages 626–662)Abstracts of the 9th International Conference on Cachexia, Sarcopenia and Muscle Wasting, Berlin, Germany, 10–11 December 2016 (part 1) (pages 626–662)
Abstracts of the 9th International Conference on Cachexia, Sarcopenia and Muscle Wasting, Berlin, Germany, 10–11 December 2016 (part 1) (pages 626–662)

 

de Lima Junior, E. A., Yamashita, A. S., Pimentel, G. D., De Sousa, L. G. O., Santos, R. V. T., Gonçalves, C. L., Streck, E. L., de Lira, F. S., and Rosa Neto, J. C. (2016) Doxorubicin caused severe hyperglycaemia and insulin resistance, mediated by inhibition in AMPk signalling in skeletal muscle. Journal of Cachexia, Sarcopenia and Muscle, 7: 615–625. doi: 10.1002/jcsm.12104.

ABSTRACT | FULL HTML | PDF|

 
 

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