Volume 8 / Number 5 / October 2017

 

     Page 675–680

Stephan von Haehling, Nicole Ebner, Stefan D. Anker

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

 

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

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     Page 681–685

Maggie C. Walter, Peter Reilich

Recent developments in Duchenne muscular dystrophy: facts and numbersno abstract

 

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

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     Page 686–701

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

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

 

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

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     Page 702–712

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

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

 

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

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     Page 713–726

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

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

 

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

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     Page 727–734

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

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

 

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

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     Page 735–747

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

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

 

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

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     Page 748–758

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

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

 

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

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     Page 702–712

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

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

 

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

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     Page 768–777

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

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

 

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

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     Page 778–788

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

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

 

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

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     Page 789–797

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

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

 

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

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     Page 798–807

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

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

 

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

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     Page 808–823

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

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

 

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

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     Page 824–838

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

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

 

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

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     Page 839–850

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

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

 

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

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     Page 851–852

Junichi Ishida, Masakazu Saitoh, Jochen Springer

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

 

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

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     Page 853–854

Masakazu Saitoh, Junichi Ishida, Jochen Springer

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

 

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

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