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     Article first published online:  21 JUN 2017

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

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

 

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

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     Article first published online:  18 JUN 2017

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, doi: 10.1002/jcsm.12220.

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     Article first published online:  18 JUN 2017

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

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

 

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

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     Article first published online:  14 JUN 2017

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, doi: 10.1002/jcsm.12201.

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     Article first published online:  12 JUN 2017

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, doi: 10.1002/jcsm.12219.

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     Article first published online:  12 JUN 2017

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, doi: 10.1002/jcsm.12202.

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     Article first published online:  12 JUN 2017

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, doi: 10.1002/jcsm.12202.

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     Article first published online:  8 JUN 2017

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

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

 

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

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     Article first published online:  16 MAY 2017

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

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

 

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

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     Article first published online:  15 MAY 2017

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

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

 

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

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     Article first published online:  10 MAY 2017

Milan Holecek

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

 

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

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     Article first published online:  10 MAY 2017

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, doi: 10.1002/jcsm.12206.

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     Article first published online:  4 MAY 2017

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

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

 

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

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     Article first published online:  26 APR 2017

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

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

 

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

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     Article first published online:  16 APR 2017

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) RIα subunit was largely removed from, while PKA RIIα and RIIβ 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 RIα and reduced PKA RIIα 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, doi: 10.1002/jcsm.12204.

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     Article first published online:  5 APR 2017

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. HIF1α, which is activated by hypoxia, augmented the promoter activity of FABP4, together with HIF1β. 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, doi: 10.1002/jcsm.12203.

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     Article first published online:  5 APR 2017

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

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

 

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

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     Article first published online:  29 MAR 2017

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

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

 

 

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

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     Article first published online:  18 MAR 2017

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

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

 

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

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     Article first published online:  15 MAR 2017

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

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

 

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

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     Article first published online:  1 MAR 2017

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

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

 

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

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     Article first published online:  1 MAR 2017

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

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

 

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

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     Article first published online:  27 FEB 2017

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

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

 

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

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