Online First Article

Volume 5 (2014)

Number 1 / March 2014

     Page 1 - 3

Stefan D. Anker, Andrew J. S. Coats, John E. Morley, Giuseppe Rosano, Roberto Bernabei, Stephan von Haehling, Kamyar Kalantar-Zadeh
 
Muscle wasting disease: a proposal for a new disease classificationMuscle wasting and cachexia are the ultimate consequence of aging and a variety of acute and chronic illnesses. Significant efforts are made by many stakeholders to develop effective therapies. An important aspect of successful therapeutic development research is a common nomenclature for effective communication between researchers and clinicians, to the public, and also with regulatory bodies. Despite several efforts to develop consensus definitions for cachexia and sarcopenia, including such new terms for muscle wasting as myopenia, a common conceptual approach and acceptable vocabulary and classification system are yet to be established. Notwithstanding the potential need to translate such disease definitions and terminologies into different languages, we advocate the use of the term “muscle wasting” as the unifying entity that represents the single most common disease process across a large spectrum of cachexia and in sarcopenia-associated disorders. In this paper, we outline a first proposal for the disease nomenclature and classification of “Muscle Wasting Diseases.” This concept can be applied in acute and chronic disease settings. It is pertinent for wasting diseases, cachexia, and sarcopenia of any severity and due to any underlying illness. The concept of muscle wasting disease underscores the most common denominator of the underlying wasting processes, i.e., muscle wasting, without ignoring the advanced disease states that are also accompanied by fat tissue wasting. The term muscle wasting disease is easily understood by both the scientific community and the lay public. This may promote its general use and efforts to heighten education and awareness in the field.
 
Anker S.D., Coats A. J. S. , Morley J. E. , Rosano G., Bernabei R., von Haehling S., Kalantar-Zadeh K., Muscle wasting disease: a proposal for a new disease classification, J Cachex Sarcopenia Muscle 2014;1:1-3

     Page 5 - 8

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

 
Morley J. E., von Haehling S, Anker S.D, Vellas B., From sarcopenia to frailty: a road less traveled, J Cachex Sarcopenia Muscle 2014;1:5-8

     Page 9 - 18

Steven B. Heymsfield, Michael Adamek, M. Cristina Gonzalez, Guang Jia, Diana M. Thomas

Assessing skeletal muscle mass: historical overview and state of the artBackground
Even though skeletal muscle (SM) is the largest body compartment in most adults and a key phenotypic marker of sarcopenia and cachexia, SM mass was until recently difficult and often impractical to quantify in vivo. This review traces the historical development of SM mass measurement methods and their evolution to advances that now promise to provide in-depth noninvasive measures of SM composition.
Methods
Key steps in the advancement of SM measurement methods and their application were obtained from historical records and widely cited publications over the past two centuries. Recent advances were established by collecting information on notable studies presented at scientific meetings and their related publications.
Results
The year 1835 marks the discovery of creatine in meat by Chevreul, a finding that still resonates today in the D3-creatine method of measuring SM mass. Matiegka introduced an anthropometric approach for estimating SM mass in 1921 with the vision of creating a human “capacity” marker. The 1940s saw technological advances eventually leading up to the development of ultrasound and bioimpedance analysis methods of quantifying SM mass in vivo. Continuing to seek an elusive SM mass “reference” method, Burkinshaw and Cohn introduced the whole-body counting-neutron activation analysis method and provided some of the first detailed reports of cancer cachexia in the late 1970s. Three transformative breakthroughs leading to the current SM mass reference methods appeared in the 1970s and early 1980s as follows: the introduction of computed tomography (CT), photon absorptiometry, and magnetic resonance (MR) imaging. Each is advanced as an accurate and/or practical approach to quantifying whole-body and regional SM mass across the lifespan. These advances have led to a new understanding of fundamental body size-SM mass relationships that are now widely applied in the evaluation and monitoring of patients with sarcopenia and cachexia. An intermediate link between SM mass and function is SM composition. Advances in water-fat MR imaging, diffusion tensor imaging, MR elastography, imaging of connective tissue structures by ultra-short echo time MR, and other new MR approaches promise to close the gap that now exists between SM anatomy and function.
Conclusions
The global efforts of scientists over the past two centuries provides us with highly accurate means by which to measure SM mass across the lifespan with new advances promising to extend these efforts to noninvasive methods for quantifying SM composition.

Heymsfield S. B., Adamek M., Gonzalez M.C., Jia G., Thomas D.M. Assessing skeletal muscle mass: historical overview and state of the art, J Cachex Sarcopenia Muscle 2014;1:9-18

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     Page 19 - 25

M. Sheffield-Moore, E. L. Dillon, K. M. Randolph, S. L. Casperson, G. R. White, K. Jennings, J. Rathmacher, S. Schuette, M. Janghorbani, R. J. Urban, V. Hoang, M. Willis, W. J. Durham

Isotopic decay of urinary or plasma 3-methylhistidine as a potential biomarker of pathologic skeletal muscle lossBackground
Skeletal muscle loss accompanying aging or cancer is associated with reduced physical function and predicts morbidity and mortality. 3-Methylhistidine (3MH) has been proposed as a biomarker of myofibrillar proteolysis, which may contribute to skeletal muscle loss.
Methods
We hypothesized that the terminal portion of the isotope decay curve following an oral dose of isotopically labeled 3MH can be measured non-invasively from timed spot urine samples. We investigated the feasibility of this approach by determining isotope enrichment in spot urine samples and corresponding plasma samples and whether meat intake up to the time of dosing influences the isotope decay.
Results
Isotope decay constants (k) were similar in plasma and urine, regardless of diet. Post hoc comparison of hourly sampling over 10 h with three samples distributed over 10 or fewer hours suggests that three distributed samples over 5–6 h of plasma or urine sampling yield decay constants similar to those obtained over 10 h of hourly sampling.
Conclusion
The findings from this study suggest that an index of 3MH production can be obtained from an easily administered test involving oral administration of a stable isotope tracer of 3MH followed by three plasma or urine samples collected over 5–6 h the next day.

Sheffield-Moore M., Dillon E. L. , Randolph K. M. , Casperson S. L. , White G. R. , Jennings K., Rathmacher J., Schuette S., Janghorbani M., Urban R. J. , Hoang V., Willis M., Durham W. J, Isotopic decay of urinary or plasma 3-methylhistidine as a potential biomarker of pathologic skeletal muscle loss, J Cachex Sarcopenia Muscle 2014;1:19-25

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  Page 27 - 34

Céline M. H. Op den Kamp, Dirk K. M. De Ruysscher, Marieke van den Heuvel, Meike Elferink, Ruud M. A. Houben, Cary J. G. Oberije, Gerben P. Bootsma, Wiel H. Geraedts, Cordula C. M. Pitz, Ramon C. Langen, Emiel F. M. Wouters, Annemie M. W. J. Schols, Anne-Marie C. Dingemans

Highlights from the 7th Cachexia Conference: muscle wasting pathophysiological detection and novel treatment strategiesThis article highlights preclinical and clinical studies in the field of wasting disorders that were presented at the 7th Cachexia Conference
held in Kobe, Japan, in December 2013. This year, the main topics were the development of new methods and new biomarkers in the field of cachexia
and wasting disorders with particular focus on inflammatory pathways, growth differentiation factor-15, myostatin, the ubiquitin proteasome-dependent
pathway, valosin and the regulation of ubiquitin-specific protease 19 that is involved in the differentiation of myogenin and myosin heavy chain.
This article presents highlights from the development of drugs that have shown potential in the treatment of wasting disorders, particularly the ghrelin receptor agonist
anamorelin, the myostatin antagonist REGN1033, the selective androgen receptor modulators enobosarm and TEI-E0001, and the anabolic catabolic transforming agent espindolol.
In addition, novel data on the prevalence and detection methods of muscle wasting/sarcopenia are presented, including the D3-creatine dilution method and several new biomarkers.
 
Op den Kamp C. M. H. , De Ruysscher D. K. M. , van den Heuvel M. , Elferink M., Houben R. M. A. , Oberije C. J. G. , Bootsma G. P. , Geraedts W. H. , Pitz C. C. M. , Langen R. C. , Wouters E. F. M. , Schols A. M. W. J. , Dingemans A.-M. C., Highlights from the 7th Cachexia Conference: muscle wasting pathophysiological detection and novel treatment strategies, J Cachex Sarcopenia Muscle 2014;1:27-34

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     Page 35 - 78

Abstracts of the 7th Cachexia Conference, Kobe/Osaka, Japan, December 9–11, 2013 (Part 2)

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     Page 79 - 81

Everardo Treviño-Aguirre, Teresa López-Teros, Luis Gutiérrez-Robledo, Maurits Vandewoude, Mario Pérez-Zepeda

 
Treviño-Aguirre E., López-Teros T., Gutiérrez-Robledo L., Vandewoude M., Pérez-Zepeda M., Availability and use of dual energy X-ray absorptiometry (DXA) and bio-impedance analysis (BIA) for the evaluation of sarcopenia by Belgian and Latin American geriatricians, J Cachex Sarcopenia Muscle 2014;1:79-81

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Number 2 / June 2014

     Page 83 - 87

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

 
Morley J. E. , von Haehling S., Anker S.D.,  Are we closer to having drugs to treat muscle wasting disease?, J Cachex Sarcopenia Muscle 2014;2:83-87

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     Page 89 - 94

Jane B. Hopkinson

Psychosocial impact of cancer cachexiaBackground
Cancer cachexia has impact on patients and their family members. Patients experience loss of weight often accompanied by anorexia and other debilitating symptoms that have clinical impact and impact everyday life. The importance of understanding this impact lies in (1) the alleviation of cachexia-related suffering and (2) its implications for treating cachexia.
Review
Two decades of exploratory investigation of the manifestations, meaning and management of cancer cachexia reveal emotional and social impacts for both patients and their carers. Patients can describe change in appearance and loss of physical strength often accompanied by change in eating habits (amount, type and pattern of food intake). The psychosocial effects can include loss of independence, sense of failure, sense of helplessness, conflict with family members over food, social isolation and thoughts of death. They are effects that can distress. Conversely, weight loss, especially early in its course and for those who are obese, can be perceived as beneficial, which inhibits self-management of diet and physical activity.
Conclusion
Models of the psychosocial effects of cancer cachexia have been developed, leading to, as yet unproven, propositions of how negative patient and family impacts can be addressed. This literature overlooks the potential importance of psychosocial intervention to emerging multimodal treatments for the multicausal syndrome. Psychosocial intervention in cachexia should be tested for potential to help people affected by cancer cachexia feel better but also for potential to make people better by aiding uptake and compliance with multimodal therapy.
 
Hopkinson J.B.,  Psychosocial impact of cancer cachexia, J Cachex Sarcopenia Muscle 2014;2:89-94

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     Page 95 - 104

Seyyed M. R. Kazemi-Bajestani, Harald Becher, Konrad Fassbender, Quincy Chu, Vickie E. Baracos

Concurrent evolution of cancer cachexia and heart failure: bilateral effects existCancer cachexia is defined as a multifactorial syndrome of involuntary weight loss characterized by an ongoing loss of skeletal muscle mass and progressive functional impairment. It is postulated that cardiac dysfunction/atrophy parallels skeletal muscle atrophy in cancer cachexia. Cardiotoxic chemotherapy may additionally result in cardiac dysfunction and heart failure in some cancer patients. Heart failure thus may be a consequence of either ongoing cachexia or chemotherapy-induced cardiotoxicity; at the same time, heart failure can result in cachexia, especially muscle wasting. Therefore, the subsequent heart failure and cardiac cachexia can exacerbate the existing cancer-induced cachexia. We discuss these bilateral effects between cancer cachexia and heart failure in cancer patients. Since cachectic patients are more susceptible to chemotherapy-induced toxicity overall, this may also include increased cardiotoxicity of antineoplastic agents. Patients with cachexia could thus be doubly unfortunate, with cachexia-related cardiac dysfunction/heart failure and increased susceptibility to cardiotoxicity during treatment. Cardiovascular risk factors as well as pre-existing heart failure seem to exacerbate cardiac susceptibility against cachexia and increase the rate of cardiac cachexia. Hence, chemotherapy-induced cardiotoxicity, cardiovascular risk factors, and pre-existing heart failure may accelerate the vicious cycle of cachexia-heart failure. The impact of cancer cachexia on cardiac dysfunction/heart failure in cancer patients has not been thoroughly studied. A combination of serial echocardiography for detection of cachexia-induced cardiac remodeling and computed tomography image analysis for detection of skeletal muscle wasting would appear a practical and non-invasive approach to develop an understanding of cardiac structural/functional alterations that are directly related to cachexia.
 
Kazemi-Bajestani S.M. R. , Becher H.,, Fassbender K., Chu Q., Baracos V. E., Concurrent evolution of cancer cachexia and heart failure: bilateral effects exist, J Cachex Sarcopenia Muscle 2014;2:95-104

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     Page 105 - 110

Patrícia Lopes de Campos-Ferraz, Isabel Andrade, Willian das Neves, Isabela Hangai, Christiano Robles Rodrigues Alves, Antonio Herbert Lancha Jr

An overview of amines as nutritional supplements to counteract cancer cachexiaCancer cachexia is a complex multifactorial syndrome characterized by loss of skeletal muscle mass (with or without loss of fat mass) that cannot be fully reversed by conventional nutritional support and leads to progressive functional impairment. Recently, some amino acids and other amine dietary supplements have been highlighted in medical field due to positive effects upon diseases evolving skeletal muscle atrophy. Therefore, the aim of this brief review is to discuss the putative application of amines as dietary supplements to counteract skeletal muscle wasting on cancer cachexia. Specifically, we focus in two nutritional supplements: (1) branched-chain amino acids (BCAAs) and (2) creatine. Both BCAAs and creatine may attenuate proteolysis and enhance proteins synthesis in skeletal muscle. Although more experimental studies and clinical trials are still necessary to elucidate this therapeutic application, several evidences have demonstrated that amines supplementation is a promising coadjuvant treatment to cancer cachexia.
 
Lopes de Campos-Ferraz P., Andrade I., das Neves W., Hangai I.,  Alves C.R.R., Lancha A.H. Jr , An overview of amines as nutritional supplements to counteract cancer cachexia , J Cachex Sarcopenia Muscle 2014;2:105-110

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     Page 111 - 120

Yorgi Mavros, Shelley Kay, Kylie A. Simpson, Michael K. Baker, Yi Wang, Ren R. Zhao,Jacinda Meiklejohn, Mike Climstein, Anthony J. O’Sullivan, Nathan de Vos, Bernhard T. Baune, Steven N. Blair, David Simar, Kieron Rooney, Nalin A. Singh, Maria A. Fiatarone Singh

Reductions in C-reactive protein in older adults with type 2 diabetes are related to improvements in body composition following a randomized controlled trial of resistance trainingBackground
Reductions in skeletal muscle mass and increased adiposity are key elements in the aging process and in the pathophysiology of several chronic diseases. Systemic low grade inflammation associated with obesity has been shown to accelerate the age-related decline in skeletal muscle. The aim of this investigation was to determine the effects of 12 months of progressive resistance training (PRT) on systemic inflammation, and whether reductions in systemic inflammation were associated with changes in body composition. We hypothesized that reductions in systemic inflammation following 12 months of PRT in older adults with type 2 diabetes would be associated with reductions in adiposity and increases in skeletal muscle mass.
Methods
Participants (n = 103) were randomized to receive either PRT or sham-exercise, 3 days a week for 12 months. C-reactive protein (CRP) was used to assess systemic inflammation. Skeletal muscle mass and total fat mass were determined using bioelectrical impedance.
Results
Twelve months of PRT tended to reduce CRP compared to sham exercise (β = −0.25, p = 0.087). Using linear mixed-effects models, the hypothesized relationships between body composition adaptations and CRP changes were significantly stronger for skeletal muscle mass (p = 0.04) and tended to be stronger for total fat mass (p = 0.07) following PRT when compared to sham-exercise. Using univariate regression models, stratified by group allocation, reductions in CRP were associated with increases in skeletal muscle mass (p = 0.01) and reductions in total fat mass (p = 0.02) in the PRT group, but not in the sham-exercise group (p = 0.87 and p = 0.32, respectively).
Conclusions
We have shown for the first time that reductions in systemic inflammation in older adults with type 2 diabetes following PRT were associated with increases in skeletal muscle mass. Furthermore, reductions in CRP were associated with reductions in adiposity, but only when associated with PRT. Lifestyle interventions aimed at reducing systemic inflammation in older adults with type 2 diabetes should therefore incorporate anabolic exercise such as PRT to optimize the anti-inflammatory benefits of favorable body composition adaptations.
 
Mavros Y., Kay S., Simpson K. A., Baker M. K., Wang Y., Zhao R. R., Meiklejohn J., Climstein M., O’Sullivan A. J., de Vos N., Baune B. T., Blair S. N., Simar D., Rooney K., Singh N. A., Singh M. A. F., Reductions in C-reactive protein in older adults with type 2 diabetes are related to improvements in body composition following a randomized controlled trial of resistance training, J Cachex Sarcopenia Muscle 2014;2:111-120

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     Page 121 - 125

Tammy Wanger, Nathan R. Foster, Phuong L. Nguyen, Aminah Jatoi

Patients’ rationale for declining participation in a cancer-associated weight loss studyBackground
Fewer than 5 % of cancer patients participate in clinical research. Although this paltry rate has led to extensive research on this topic, previous studies have not sought verbatim comments in a real-time, comprehensive manner to understand why patients decline.
Methods
This study used a low-risk, non-interventional parent study that focused on cancer-associated weight loss to understand patients’ reasons for declining research participation. A research assistant wrote down the name and verbatim reason of all patients who declined to participate. These comments with accompanying patient demographic data are the subject of this report.
Results
Of the 334 patients, 51 (15 %) declined parent study enrollment; three comment-related themes emerged: (1) a repelling sense of too much institutional research, (2) overwhelming personal health issues, and (3) a low likelihood of returning to the institution. In univariate and multivariate analyses, only age (older) and gender (female) were associated with non-enrollment. Interestingly, 41 patients with fatigue scores of 7 or worse and 26 with pain scores of 7 or worse were enrolled.
Conclusions
Although many factors were associated with declining to participate in research, symptom severity was not. Upfront education might help cancer patients better prioritize their participation in research, particularly as some patients felt overwhelmed by too much research in the institution; and for now, investigators should continue to keep asking patients for their participation.
 
Wanger T., Foster N.R., Nguyen P. L., Jatoi A., Patients’ rationale for declining participation in a cancer-associated weight loss study, J Cachex Sarcopenia Muscle 2014;2:121-125

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     Page 127 - 137

Céline M. H. Op den Kamp, Dirk K. M. De Ruysscher, Marieke van den Heuvel, Meike Elferink, Ruud M. A. Houben, Cary J. G. Oberije, Gerben P. Bootsma, Wiel H. Geraedts, Cordula C. M. Pitz, Ramon C. Langen, Emiel F. M. Wouters, Annemie M. W. J. Schols, Anne-Marie C. Dingemans

Early body weight loss during concurrent chemo-radiotherapy for non-small cell lung cancerBackground and purpose
Radiation-esophagitis and weight loss are frequently observed toxicities in patients treated with concurrent chemo-radiotherapy (CT-RT) for non-small cell lung cancer (NSCLC) and might be related. The purpose was to investigate whether weight loss already starts early after initiation of CT-RT and precedes radiation-esophagitis.
Materials and methods
In a retrospective cohort, weight and esophagitis grade ≥2 were assessed during the first weeks of (CT-)RT in patients treated with concurrent (n = 102) or sequential (n = 92) therapy. In a prospective validation study, data on body weight, esophagitis grade ≥2, nutritional intake and muscle strength were obtained before, during and following CT-RT.
Results
In the retrospective cohort, early weight loss was observed in concurrently treated patients (p = 0.002), independent of esophagitis ≥ grade 2. Early weight loss was also observed in the prospective cohort (p = 0.003) and was not accompanied by decreases in nutritional intake. In addition lower limb muscle strength rapidly declined (p = 0.042). In the later weeks of treatment, further body weight loss occurred (p < 0.001) despite increased nutritional supplementation and body weight was only partly recovered after 4 weeks post CT-RT (p = 0.003).
Conclusions
Weight loss during concurrent CT-RT for NSCLC starts early and prior to onset of esophagitis, requiring timely and intense nutritional rehabilitation.
 
Op den Kamp C. M. H., De Ruysscher D. K. M., van den Heuvel M., Elferink M., Houben R. M. A., Oberije C. J. G., Bootsma G. P., Geraedts W. H., Pitz C. C. M., Langen R. C., Wouters E. F. M., Schols A. M. W. J., Dingemans A.-M. C., Early body weight loss during concurrent chemo-radiotherapy for non-small cell lung cancer, J Cachex Sarcopenia Muscle 2014;2:127-137

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     Page 139 - 148

Maren S. Fragala, Adam R. Jajtner, Kyle S. Beyer, Jeremy R. Townsend, Nadia S. Emerson, Tyler C. Scanlon, Leonardo P. Oliveira, Jay R. Hoffman, Jeffrey R. Stout

Biomarkers of muscle quality: N-terminal propeptide of type III procollagen and C-terminal agrin fragment responses to resistance exercise training in older adultsBackground
N-terminal peptide of procollagen type III (P3NP) and C-terminal agrin fragment (CAF) are circulating biomarkers that are related to lean body mass in older adults. P3NP is a circulating marker reflective of muscular structural remodeling while CAF is a circulating marker of neuromuscular remodeling. As resistance exercise is an established intervention that can effectively improve muscle quality, we sought to evaluate circulating biomarker changes corresponding to a resistance exercise intervention in older adults.
Methods
Twenty-three older adults (aged 61 to 85 years) were randomized into an intervention (6-week resistance training) or control group. Resting circulating P3NP, CAF, lean body mass (LBM), muscle cross-sectional area (CSA), muscle strength, and muscle quality were determined at baseline and after the intervention or control period by enzyme-linked immunosorbent assay, dual-energy X-ray absorptiometry, ultrasound, leg extension, and relative strength, respectively. Changes in circulating biomarkers and measures of muscle mass and quality were evaluated with repeated-measures analysis of variance; clinical interpretations were made with magnitude-based inferences, and relationships between variables were evaluated with bivariate correlations.
Results
The short-term resistance exercise intervention was effective at improving muscle quality by 28 % (p < 0.001) despite no significant changes in lean body mass. Baseline circulating P3NP was somewhat lower in older women (4.15 ± 1.9 ng/mL) compared with older men (4.81 ± 2.1 ng/mL). The exercise intervention tended to increase circulating P3NP (baseline = 4.53 ± 1.80 to post = 4.88 ± 1.86) and was significantly correlated with changes in LBM (r = 0.422, p = 0.045). At baseline, women (3.91 ± 1.12 pg/mL) had somewhat higher circulating CAF than men (3.47 ± 1.37 pg/mL). Circulating CAF increased by 10.4 % (3.59 to 4.00 pg/ml) in older adults following 6 weeks of resistance exercise training. Changes in circulating CAF were significantly related to changes in CSA of the vastus lateralis (r = 0.542, p = 0.008).
Conclusions
Assessment of P3NP and CAF from blood samples may provide minimally invasive and clinically informative measures of skeletal muscle status in older adults. Circulating CAF appears to increase in response to short-term resistance exercise training in older adults to a clinically meaningful magnitude. Changes in circulating P3NP in response to the intervention were less clear but appear to reflect muscle hypertrophy. Further research is needed to elucidate whether P3NP, CAF, or other biomarkers can reflect muscle qualitative adaptations with larger and longer studies.
 
Fragala M. S., Jajtner A. R., Beyer K. S., Townsend J. R., Emerson N. S., Scanlon T. C., Oliveira L. P., Hoffman J. R., Stout J. R., Biomarkers of muscle quality: N-terminal propeptide of type III procollagen and C-terminal agrin fragment responses to resistance exercise training in older adults, J Cachex Sarcopenia Muscle 2014;2:139-148

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     Page 149 - 158

Mareike S. Pötsch, Anika Tschirner, Sandra Palus, Stephan von Haehling, Wolfram Doehner, John Beadle, Andrew J. S. Coats, Stefan D. Anker, Jochen Springer

The anabolic catabolic transforming agent (ACTA) espindolol increases muscle mass and decreases fat mass in old ratsBackground
Sarcopenia, the age-related, progressive loss of skeletal muscle mass, strength, and function, is a considerable socioeconomic burden by increasing risks of falls, fractures, and frailty. Moreover, sarcopenic patients are often obese and therapeutic options are very limited.
Methods
Here, we assessed the efficacy of espindolol on muscle mass in 19-month-old male Wistar Han rats (weight, 555 ± 18 g), including safety issues. Rats were randomized to treatment with 3 mg/kg/day espindolol (n = 8) or placebo (n = 14) for 31 days.
Results
Placebo-treated rats progressively lost body weight (−15.5 ± 7.2 g), lean mass (−1.5 ± 4.2 g), and fat mass (−15.6 ± 2.7 g), while espindolol treatment increased body weight (+8.0 ± 6.1 g, p < 0.05), particularly lean mass (+43.4 ± 3.5 g, p < 0.001), and reduced fat mass further (−38.6 ± 3.4 g, p < 0.001). Anabolic/catabolic signaling was assessed in gastrocnemius muscle. Espindolol decreased proteasome and caspase-3 proteolytic activities by approximately 50 % (all p < 0.05). Western blotting showed a reduced expression of key catabolic regulators, including NFκB, MuRF1, and LC-3 (all p < 0.01). The 50- and 26-kDa forms of myostatin were downregulated fivefold and 20-fold, respectively (both p < 0.001). Moreover, 4E-BP-1 was reduced fivefold (p < 0.01), while phospho-PI3K was upregulated fivefold (p < 0.001), although Akt expression and phosphorylation were lower compared to placebo (all p < 0.05). No regulation of p38 and expression of ERK1/2 were observed, while phosphorylation of p38 was reduced (−54 %, p < 0.001) and ERK1/2 was increased (115 and 83 %, respectively, both p < 0.01). Espindolol did not affect cardiac function (echocardiography) or clinical plasma parameters.
Conclusion
Espindolol reversed the effects of aging/sarcopenia, particularly loss of muscle mass and increased fat mass. Thus, espindolol is an attractive candidate drug for the treatment of sarcopenia patients.

Pötsch M. S., Tschirner A., Palus S., von Haehling S., Doehner W., Beadle J., Coats A. J. S., Anker S. D., Springer J., The anabolic catabolic transforming agent (ACTA) espindolol increases muscle mass and decreases fat mass in old rats, J Cachex Sarcopenia Muscle 2014;2:149-158

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     Page 159 - 169

Jvalini T. Dwarkasing, Miriam van Dijk, Francina J. Dijk, Mark V. Boekschoten, Joyce Faber, Josep M. Argilès, Alessandro Laviano, Michael Müller, Renger F. Witkamp, Klaske van Norren

Hypothalamic food intake regulation in a cancer-cachectic mouse modelBackground
Appetite is frequently affected in cancer patients leading to anorexia and consequently insufficient food intake. In this study, we report on hypothalamic gene expression profile of a cancer-cachectic mouse model with increased food intake. In this model, mice bearing C26 tumour have an increased food intake subsequently to the loss of body weight. We hypothesise that in this model, appetite-regulating systems in the hypothalamus, which apparently fail in anorexia, are still able to adapt adequately to changes in energy balance. Therefore, studying changes that occur on appetite regulators in the hypothalamus might reveal targets for treatment of cancer-induced eating disorders. By applying transcriptomics, many appetite-regulating systems in the hypothalamus could be taken into account, providing an overview of changes that occur in the hypothalamus during tumour growth.
Methods
C26-colon adenocarcinoma cells were subcutaneously inoculated in 6 weeks old male CDF1 mice. Body weight and food intake were measured three times a week. On day 20, hypothalamus was dissected and used for transcriptomics using Affymetrix chips.
Results
Food intake increased significantly in cachectic tumour-bearing mice (TB), synchronously to the loss of body weight. Hypothalamic gene expression of orexigenic neuropeptides NPY and AgRP was higher, whereas expression of anorexigenic genes CCK and POMC were lower in TB compared to controls.
In addition, serotonin and dopamine signalling pathways were found to be significantly altered in TB mice. Serotonin levels in brain showed to be lower in TB mice compared to control mice, while dopamine levels did not change. Moreover, serotonin levels inversely correlated with food intake.
Conclusions
Transcriptomic analysis of the hypothalamus of cachectic TB mice with an increased food intake showed changes in NPY, AgRP and serotonin signalling. Serotonin levels in the brain showed to correlate with changes in food intake. Further research has to reveal whether targeting these systems will be a good strategy to avoid the development of cancer-induced eating disorders.
 
Dwarkasing J. T., van Dijk M., Dijk F. J., Boekschoten M. V., Faber J., Argilès J. M., Laviano A., Müller M., Witkamp R. F., van Norren K., Hypothalamic food intake regulation in a cancer-cachectic mouse model, J Cachex Sarcopenia Muscle 2014;2:159-169

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Number 3 / September 2014

     Page 171 - 176

Stefan D. Anker, Stephan von Haehling

 
Anker S.D., von Haehling S.,Efforts begin to sprout: publications in JCSM on cachexia, sarcopenia and muscle wasting receive attention. J Cachex Sarcopenia Muscle 2014;3:171-176.

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     Page 177 - 180

Connie M. Rhee, Kamyar Kalantar-Zadeh

Resistance exercise: an effective strategy to reverse muscle wasting in hemodialysis patients?Muscle wasting is a common complication afflicting maintenance hemodialysis (HD) patients, and it is associated with decreased muscle function, exercise performance, physical function, and quality of life. Meanwhile, numerous epidemiologic studies have consistently shown that greater muscle mass (ascertained by body anthropometry surrogates, body composition tests such as dual x-ray absorptiometry, and/or serum creatinine in patients with little to no residual kidney function) is associated with increased survival in this population. The pathophysiology of muscle wasting in HD patients is complex and may be caused by poor dietary intake, catabolic effects of dialysis therapy, hormonal alterations (e.g., decreased levels or resistance to anabolic hormones, increased levels of catabolic hormones), inflammation, metabolic acidosis, and concurrent comorbidities. Muscle disuse resulting from low physical activity is an important yet under-appreciated risk factor for muscle wasting. Intra-dialytic resistance exercise training has been suggested as a potential strategy to correct and/or prevent this complication in HD patients, but prior studies examining this exercise modality as an anabolic intervention have shown mixed results. In a recently published 12-week randomized controlled trial of a novel intra-dialytic progressive resistance exercise training (PRET) program vs. control therapy conducted in HD and non-HD patients, PRET resulted in increased muscle volume and strength in both groups. At this time, further study is needed to determine if anabolic improvements imparted by resistance exercise translates into improved physical function and quality of life, decreased hospitalization and mortality risk, and greater cost-effectiveness in HD patients.

Rhee C. M., Kalantar-Zadek K.,Resistance exercise: an effective strategy to reverse muscle wasting in hemodialysis patients?. J Cachex Sarcopenia Muscle 2014;3:177-180.

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     Page 181

Denis Guttridge, Marion Couch, Sergio Di Marco, Imed E. Gallouzi, Nancy D. Zitzmann, Vickie Baracos, Michael Rudnicki, Michel Tremblay, Teresa Zimmers

 
Guttridge D., Couch M., Di Marco S., Gallouzi I.E., Zitzmann N.D., Baracos V., Rudnicki M., Tremblay M., ZimmersT., An invitation to the 2nd Cancer Cachexia Conference, Montréal, Canada. J Cachex Sarcopenia Muscle 2014;3:181.

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     Page 183 - 192

Michael J. Ormsbee, Carla M. Prado, Jasminka Z. Ilich, Sarah Purcell, Mario Siervo, Abbey Folsom, Lynn Panton

Osteosarcopenic obesity: the role of bone, muscle, and fat on health
Osteopenia/osteoporosis, sarcopenia, and obesity are commonly observed in the process of aging, and recent evidence suggests a potential interconnection of these syndromes with common pathophysiology. The term osteosarcopenic obesity has been coined to describe the concurrent appearance of obesity in individuals with low bone and muscle mass. Although our understanding of osteosarcopenic obesity’s etiology, prevalence, and consequences is extremely limited, it is reasonable to infer its negative impact in a population that is aging in an obesogenic environment. It is likely that these individuals will present with poorer clinical outcomes caused by the cascade of metabolic abnormalities associated with these changes in body composition. Clinical outcomes include but are not limited to increased risk of fractures, impaired functional status (including activities of daily living), physical disability, insulin resistance, increased risk of infections, increased length of hospital stay, and reduced survival. These health outcomes are likely to be worse when compared to individuals with obesity, sarcopenia, or osteopenia/osteoporosis alone. Interventions that utilize resistance training exercise in conjunction with increased protein intake appear to be promising in their ability to counteract osteosarcopenic obesity.
 
Ormsbee M.J., Prado C.M., Ilich J.Z., Purcell S., Siervo M., Folsom A., Panton L., Osteosarcopenic obesity: the role of bone, muscle, and fat on health. J Cachex Sarcopenia Muscle 2014;3:183-192.

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     Page 193 - 198

Sandra Palus, Stephan von Haehling, Jochen Springer

Muscle wasting: an overview of recent developments in basic research
The syndrome of cachexia, i.e., involuntary weight loss in patients with underlying diseases, sarcopenia, i.e., loss of muscle mass due to aging, and general muscle atrophy from disuse and/or prolonged bed rest have received more attention over the last decades. All lead to a higher morbidity and mortality in patients, and therefore, they represent a major socio-economic burden for the society today. This mini-review looks at recent developments in basic research that are relevant to the loss of skeletal muscle. It aims to cover the most significant publication of last 3 years on the causes and effects of muscle wasting, new targets for therapy development, and potential biomarkers for assessing skeletal muscle mass. The targets include the following: (1) E-3 ligases TRIM32, SOCS1, and SOCS3 by involving the elongin BC ubiquitin-ligase, Cbl-b, culling 7, Fbxo40, MG53 (TRIM72), and the mitochondrial Mul1; (2) the kinase MST1; and (3) the G-protein Gαi2. D(3)-creatine has the potential to be used as a novel biomarker that allows to monitor actual change in skeletal muscle mass over time. In conclusion, significant development efforts are being made by academic groups as well as numerous pharmaceutical companies to identify new target and biomarker muscles, as muscle wasting represents a great medical need, but no therapies have been approved in the last decades.
 
Palus S., von Haehling S., Springer J., Muscle wasting: an overview of recent developments in basic research. J Cachex Sarcopenia Muscle 2014;3:193-198.

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     Page 199 - 207

Danielle L. Kirkman, Paul Mullins, Naushad A. Junglee, Mick Kumwenda, Mahdi M. Jibani, Jamie H. Macdonald

Anabolic exercise in haemodialysis patients: a randomised controlled pilot studyBackground
The anabolic response to progressive resistance exercise training (PRET) in haemodialysis patients is unclear. This pilot efficacy study aimed to determine whether high-intensity intradialytic PRET could reverse atrophy and consequently improve strength and physical function in haemodialysis patients. A second aim was to compare any anabolic response to that of healthy participants completing the same program.
Methods
In a single blind controlled study, 23 haemodialysis patients and 9 healthy individuals were randomly allocated to PRET or an attention control (SHAM) group. PRET completed high-intensity exercise leg extensions using novel equipment. SHAM completed low-intensity lower body stretching activities using ultra light resistance bands. Exercises were completed thrice weekly for 12 weeks, during dialysis in the haemodialysis patients. Outcomes included knee extensor muscle volume by magnetic resonance imaging, knee extensor strength by isometric dynamometer and lower body tests of physical function. Data were analysed by a per protocol method using between-group comparisons.
Results
PRET elicited a statistically and clinically significant anabolic response in haemodialysis patients (PRET—SHAM, mean difference [95 % CI]: 193[63 to 324] cm3) that was very similar to the response in healthy participants (PRET—SHAM, 169[−41 to 379] cm3). PRET increased strength in both haemodialysis patients and healthy participants. In contrast, PRET only enhanced lower body functional capacity in the healthy participants.
Conclusions
Intradialytic PRET elicited a normal anabolic and strength response in haemodialysis patients. The lack of a change in functional capacity was surprising and warrants further investigation.

Kirkman D.L., Mullins P., Junglee N.A., Kumwenda M., Jibani M.M., Macdonald J.H., Anabolic exercise in haemodialysis patients: a randomised controlled pilot study. J Cachex Sarcopenia Muscle 2014;3:199-207.

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     Page 209 - 220

J. C. Kim, B. B. Shapiro, M. Zhang, Y. Li, J. Porszasz, R. Bross, U. Feroze, R. Upreti, K. Kalantar-Zadeh,J. D. Kopple

Daily physical activity and physical function in adult maintenance hemodialysis patientsBackground
Maintenance hemodialysis (MHD) patients reportedly display reduced daily physical activity (DPA) and physical performance. Low daily physical activity and decreased physical performance are each associated with worse outcomes in chronic kidney disease patients. Although daily physical activity and physical performance might be expected to be related, few studies have examined such relationships in MHD patients, and methods for examining daily physical activity often utilized questionnaires rather than activity monitors. We hypothesized that daily physical activity and physical performance are reduced and correlated with each other even in relatively healthier MHD patients.
Methods
Daily physical activity, 6-min walk distance (6-MWT), sit-to-stand, and stair-climbing tests were measured in 72 MHD patients (32 % diabetics) with limited comorbidities and 39 normal adults of similar age and gender mix. Daily physical activity was examined by a physical activity monitor. The human activity profile was also employed.
Results
Daily physical activity with the activity monitor, time-averaged over 7 days, and all three physical performance tests were impaired in MHD patients, to about 60–70 % of normal values (p < 0.0001 for each measurement). Human activity profile scores were also impaired (p < 0.0001). MHD patients spent more time sleeping or in marked physical inactivity (p < 0.0001) and less time in ≥ moderate activity (p < 0.0001). These findings persisted when comparisons to normals were restricted to men or women separately. After adjustment, daily physical activity correlated with 6-MWT but not the two other physical performance tests. Human activity profile scores correlated more closely with all three performance tests than did DPA.
Conclusions
Even in relatively healthy MHD patients, daily physical activity and physical performance are substantially impaired and correlated. Whether training that increases daily physical activity or physical performance will improve clinical outcome in MHD patients needs to be examined.

Kim J. C., Shapiro B. B., Zhang M., Li Y., Porszasz J., Bross R., Feroze U., Upreti R., Kalantar-Zadeh R., Kopple J. D.,Daily physical activity and physical function in adult maintenance hemodialysis patients. J Cachex Sarcopenia Muscle 2014;3:209-220.

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     Page 221 - 228

Sébastien Barbat-Artigas, Sophie Dupontgand, Charlotte H. Pion, Yannick Feiter-Murphy, Mylène Aubertin-Leheudre

Identifying recreational physical activities associated with muscle quality in men and women aged 50 years and overBackground
Several studies conducted in a laboratory-related environment have shown that exercise is associated with increased muscle quality in older adults. The aim of the present study was to investigate whether recreational exercise may also be associated with muscle quality in men and women aged 50 years and over.
Methods
Data are from 312 individuals (215 women) aged 50 years and older. Body composition (dual-energy X-ray absorptiometry) and knee extension strength (KES) of the right leg (one repetition maximum) were assessed. Muscle quality (MQ) (KES/right lower limb lean mass) was calculated. Recreational exercises (duration and weekly amount) were determined by structured interview.
Results
The duration of the period during which participants practiced resistance activities was the only predictor of MQ (p = 0.018) and explained an additional 1.6 % of the variance in MQ, after controlling for age and gender. Furthermore, the weekly amount of practice of aerobic activities significantly interacted with age (p < 0.001) to determine MQ.
Conclusions
Findings suggest that long-term engagement in resistance exercise is beneficial for muscle quality and should be encouraged. Furthermore, beyond 60 years, aerobic activities also seem to be positively associated with muscle quality.

Barbat-Artigas S., Dupontgand S., Pion C.H., Feiter-Murphy Y., Aubertin-Leheudre M., Identifying recreational physical activities associated with muscle quality in men and women aged 50 years and over. J Cachex Sarcopenia Muscle 2014;3:221-228.

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     Page 229 - 236

Timothy R. Henwood, Justin W. Keogh, Natasha Reid, Will Jordan, Hugh E. Senior

Assessing sarcopenic prevalence and risk factors in residential aged care: methodology and feasibilityBackground
Sarcopenia is a significant geriatric syndrome with both health care expenditure and personal burden. Most recently, the European Working Group in Sarcopenia in Older Adults has established a consensus definition and assessment criteria for sarcopenia that includes a below-normal muscle mass and muscle function (either or both of below-normal muscle strength and physical performance). Using these criteria, work is needed to identify the prevalence and risk factors among the old, and those most susceptible to sarcopenia, the very old. This manuscript describes the recruitment and data collection methodology, and direct burden to participants, among a very old cohort residing in a residential aged care (RAC) setting.
Methods
Eleven RAC facilities participated in the study. Potential participants were identified by the facility service manager and then randomised into the study. All participants gave self or substitute decision maker consent. Participants undertook a single one on one assessment that included measures of sarcopenia, functional capacity, cognitive and nutritional health, falls, activity, facility and hospital history, physical activity and assessment burden. A sub-study of physical activity and sedentary behaviours measured by activPAL3™ inclinometer was also conducted.
Results
Of 709 residents, 328 were ineligible to participate. Two hundred and seventy-three residents were randomised to the study and 102 gave informed or substitute decision maker consent. Participants were 84.5 ± 8.2 years of age and had been in care for 1,204.2 ± 1,220.1 days. The groups need for care was high (Aged Care Funding Instrument score of 2.6 ± 1.7) and they had a below-normal functional (Short Physical Performance Battery summery score of 3.5 ± 2.4). The larger percentage of participants had no depression and normal cognitive capacity. A total of 33 residents participated in the activPAL study. Each assessment took an average of 27.0 ± 7.0 min, with a low assessment burden reported by participants.
Conclusions
The successful assessment of sarcopenia and physical activity in a RAC setting is labour intensive to establish, but feasible to conduct. Low recruitment numbers and the restrictive exclusion criteria, may have limited the accuracy of this work. However, this work is a primary step in establishing the level of sarcopenia and its risk factors for those in end-of-life care.

Henwood T.R., Keogh J.W.,  Reid N., Jordan W., Hugh E. Senior, Assessing sarcopenic prevalence and risk factors in residential aged care: methodology and feasibility. J Cachex Sarcopenia Muscle 2014;3:229-236.

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     Page 237

Timothy R. Henwood, Justin W. Keogh, Natasha Reid, Will Jordan, Hugh E. Senior

 
Henwood T.R., Keogh J.W., Reid N., Jordan W., Hugh E. Senior, Erratum to: Assessing sarcopenic prevalence and risk factors in residential aged care: methodology and feasibility. J Cachex Sarcopenia Muscle 2014;3:237.

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     Page 239 - 246

S. A. Cichello, R. S. Weisinger, J. Schuijers, M. Jois

1-Sarcosine–angiotensin II infusion effects on food intake, weight loss, energy expenditure, and skeletal muscle UCP3 gene expression in a rat modelBackground
There are a myriad of proteins responsible for modulation of expenditure of energy. Angiotensin II (Ang II) is a vital component of renin-angiotensin system that affects blood pressure and also linked to both cachexia and obesity via fat and muscle metabolism. Previous research suggests that the direct action of Ang II is on the brain, via angiotensin II type 1 receptor protein, affecting food intake and energy expenditure. The objective of the study is to investigate the effect of 1-sarcosine (SAR)-Ang II infusion on energy expenditure and metabolism in a rat model of congestive heart failure cachexia.
Methods
Adult female rats of the Sprague Dawley strain (n = 33) were used (11 pair-fed control, 12 ad libitum and 10, 1-sarcosine–angiotensin II-infused rats). Body weight, faecal excretion, feed intake (in grams), water intake (in milliliters) and urine excreted were recorded daily. The measurements were recorded in three different periods (4 days prior to surgery, “pre-infusion”; day of surgery and 5 days postsurgery, “infusion period”; days 7 to 14, “recovery” period). Different analytical methods were used to measure energy expenditure per period, uncoupling protein 3 mRNA expression, crude protein and adipose tissue body composition.
Results
During the infusion period, the SAR–Ang II group experienced rapid weight loss (p < 0.05) in comparison to the ad libitum and pair-fed groups. The SAR–Ang II group displayed lower (p < 0.05) body fat content (in percent) than the controls. There was also increased (p < 0.05) uncoupling protein 3 (UCP3) mRNA expression in the SAR–Ang II group and pair-fed group when compared to the controls.
Conclusion
In summary, the results suggest that SAR–Ang II infusion impairs appetite and decreases body weight by wasting predominantly adipose tissue, which may be due to elevated energy expenditure via mitochondrial uncoupling (UCP3 protein activity).

Cichello S. A., Weisinger R. S., Schuijers J., Jois M., 1-Sarcosine–angiotensin II infusion effects on food intake, weight loss, energy expenditure, and skeletal muscle UCP3 gene expression in a rat mod. J Cachex Sarcopenia Muscle 2014;3:239-246.

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     Page 247 - 249

Akihiko Kato, Takako Takita, Hiromichi Kumagai

 
Kato A., Takita T., Kumagai H., Relationship between arterial stiffening and skeletal muscle atrophy in hemodialysis patients: a gender comparative study, J Cachex Sarcopenia Muscle 2014;3:247-249.

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     Page 251 - 252

Alessio Molfino, Alessia Papa, Maria L. Gasperini-Zacco, Maurizio Muscaritoli, Antonio Amoroso, Antonia Cascino, Carlo Catalano, Carlina V. Albanese, Alessandro Laviano

 
Molfino A., Papa A., Gasperini-Zacco M.L., Muscaritoli M., Amoroso A., Cascino A., Catalano C., Albanese C.V., Laviano A., Left ventricular mass correlates with lean body mass in patients with disease-associated wasting, J Cachex Sarcopenia Muscle 2014;3:251-252.

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Number 4 / December 2014

     Page 253 - 259

John E. Morley, Stefan D. Anker

Prevalence, incidence, and clinical impact of sarcopenia: facts, numbers, and epidemiology—update 2014Sarcopenia is now defined as a decline in walking speed or grip strength associated with low muscle mass. Sarcopenia leads to loss of mobility and function, falls, and mortality. Sarcopenia is a major cause of frailty, but either condition can occur without the other being present. Sarcopenia is present in about 5 to 10 % of persons over 65 years of age. It has multiple causes including disease, decreased caloric intake, poor blood flow to muscle, mitochondrial dysfunction, a decline in anabolic hormones, and an increase in proinflammatory cytokines. Basic therapy includes resistance exercise and protein and vitamin D supplementation. There is now a simple screening test available for sarcopenia—SARC-F. All persons 60 years and older should be screened for sarcopenia and treated when appropriate.

Morley J.E., Anker S.D., Prevalence, incidence, and clinical impact of sarcopenia: facts, numbers, and epidemiology—update 2014. J Cachex Sarcopenia Muscle 2014;4:253-259.

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     Page 261 - 263

Stephan von Haehling, Stefan D. Anker

Prevalence, incidence and clinical impact of cachexia: facts and numbers—update 2014Cachexia is a serious but underrecognised consequence of many chronic diseases. Its prevalence ranges from 5–15 % in end-stage chronic heart failure to 50–80 % in advanced cancer. Cachexia is also part of the terminal course of many patients with chronic kidney disease, chronic obstructive pulmonary disease (COPD) and rheumatoid arthritis. Mortality rates of patients with cachexia range from 10–15 % per year in COPD through 20–30 % per year in chronic heart failure and chronic kidney disease to 80 % in cancer. The condition is also associated with poor quality of life. In the industrialised world, the overall prevalence of cachexia (due to any disease and not necessarily associated with hospital admission) is growing and it currently affects around 1 % of the patient population, i.e. around 9 million people. It is also a significant health problem in other parts of the globe. Recently there have been advances in our understanding of the multifactorial nature of the condition, and particularly of the role of inflammatory mediators and the imbalance of anabolism and catabolism. Several promising approaches to treatment have failed to live up to the challenge of phase III clinical trials, but the ghrelin receptor agonist anamorelin seems to have fulfilled at least some early promise. Further advances are urgently needed.

von Haehling S., Anker S.D., Prevalence, incidence and clinical impact of cachexia: facts and numbers—update 2014. J Cachex Sarcopenia Muscle 2014;4:261-263.

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     Page 265 - 268

David Rhys Alchin

Sarcopenia: describing rather than defining a conditionBackground
Traditional definitions of sarcopenia have described an aging-associated disorder roughly defined as muscle mass two standard deviations below the young adult demographic. In an effort to clear the ambiguity pertaining to such descriptions, two international bodies have put forth working definitions of sarcopenia, namely The Society of Sarcopenia, Cachexia and Wasting Disorders in 2011, and The European Working Group on Sarcopenia in Older People in 2009.
Review
This paper will look at the current zeitgeist of sarcopenia through a range of studies and will argue that what we have is an amalgamated and often conflicted description, rather than a definition, of the sarcopenic condition. Herein, we will consider whether such descriptions of sarcopenia should center on the consideration of the neuromuscular junction (NMJ) rather than describing the condition more in terms of muscular pathology.
Conclusion
Consideration was given to studies of the NMJ to advance the idea that present notions of the sarcopenic condition are incomplete and that at its’ core, sarcopenia is an age-related disorder of the NMJ.
 
Alchin D.R.., Sarcopenia: describing rather than defining a condition. J Cachex Sarcopenia Muscle 2014;4:265-268.

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     Page 269 - 277

Hidetaka Wakabayashi, Kunihiro Sakuma

Rehabilitation nutrition for sarcopenia with disability: a combination of both rehabilitation and nutrition care managementMalnutrition and sarcopenia often occur in rehabilitation settings. The prevalence of malnutrition and sarcopenia in older patients undergoing rehabilitation is 49–67 % and 40–46.5 %, respectively. Malnutrition and sarcopenia are associated with poorer rehabilitation outcome and physical function. Therefore, a combination of both rehabilitation and nutrition care management may improve outcome in disabled elderly with malnutrition and sarcopenia. The concept of rehabilitation nutrition as a combination of both rehabilitation and nutrition care management and the International Classification of Functioning, Disability and Health guidelines are used to evaluate nutrition status and to maximize functionality in the elderly and other people with disability. Assessment of the multifactorial causes of primary and secondary sarcopenia is important because rehabilitation nutrition for sarcopenia differs depending on its etiology. Treatment of age-related sarcopenia should include resistance training and dietary supplements of amino acids. Therapy for activity-related sarcopenia includes reduced bed rest time and early mobilization and physical activity. Treatment for disease-related sarcopenia requires therapies for advanced organ failure, inflammatory disease, malignancy, or endocrine disease, while therapy for nutrition-related sarcopenia involves appropriate nutrition management to increase muscle mass. Because primary and secondary sarcopenia often coexist in people with disability, the concept of rehabilitation nutrition is useful for their treatment. Stroke, hip fracture, and hospital-associated deconditioning are major causes of disability, and inpatients of rehabilitation facilities often have malnutrition and sarcopenia. We review the concept of rehabilitation nutrition, the rehabilitation nutrition options for stroke, hip fracture, hospital-associated deconditioning, sarcopenic dysphagia, and then evaluate the amount of research interest in rehabilitation nutrition.
 
Wakabayashi H., Sakuma K., Rehabilitation nutrition for sarcopenia with disability: a combination of both rehabilitation and nutrition care management. J Cachex Sarcopenia Muscle 2014;4:269-277.

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     Page 278 - 285

Josep M. Argilés, Cibely Cristine Fontes-Oliveira, Miriam Toledo, Francisco J. López-Soriano, Sílvia Busquets

 
Argilés J.M., Fontes-Oliveira C.C., Toledo M., López-Soriano F.J., Busquets S., Cachexia: a problem of energetic inefficiency. J Cachex Sarcopenia Muscle 2014;4:278-285.

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     Page 287 - 296

Krystian Josiak, Ewa A. Jankowska, Massimo F. Piepoli, Waldemar Banasiak, Piotr Ponikowski

Skeletal myopathy in patients with chronic heart failure: significance of anabolic-androgenic hormonesIn heart failure, impairment of cardiac muscle function leads to numerous neurohormonal and metabolic disorders, including an imbalance between anabolic and catabolic processes, in favour of the latter. These disorders cause loss of muscle mass with structural and functional changes within the skeletal muscles, known as skeletal myopathy. This phenomenon constitutes an important mechanism that participates in the pathogenesis of chronic heart failure. both its clinical symptoms and the progression of the disease. Attempts to reverse the above-mentioned pathologic processes by exploiting the anabolic action of androgenic hormones could provide a potentially attractive treatment option. The current concepts of anabolic androgen deficiency and resultant skeletal myopathy in patients with heart failure are reviewed, and the potential role of anabolic-androgenic hormones as an emerging therapeutic option for targeting heart failure is discussed.
 
Josiak K., Jankowska E.A., Piepoli M.F., Banasiak W., Ponikowski P., Skeletal myopathy in patients with chronic heart failure: significance of anabolic-androgenic hormones. J Cachex Sarcopenia Muscle 2014;4:287-296.

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     Page 297 - 305

Tuba Khawaja, Aalap Chokshi, Ruiping Ji, Tomoko S. Kato, Katherine Xu, Cynthia Zizola, Christina Wu, Daniel E. Forman, Takeyoshi Ota, Peter Kennel, Hiroo Takayama,Yoshifumi Naka, Isaac George, Donna Mancini, Christian P. Schulze

Ventricular assist device implantation improves skeletal muscle function, oxidative capacity, and growth hormone/insulin-like growth factor-1 axis signaling in patients with advanced heart failureBackground
Skeletal muscle dysfunction in patients with heart failure (HF) has been linked to impaired growth hormone (GH)/insulin-like growth factor (IGF)-1 signaling. We hypothesized that ventricular assist device (VAD) implantation reverses GH/IGF-1 axis dysfunction and improves muscle metabolism in HF.
Methods
Blood and rectus abdominis muscle samples were collected during VAD implantation and explantation from patients with HF and controls. Clinical data were obtained from medical records, biomarkers measured by enzyme-linked immunosorbent assay (ELISA), and gene expression analyzed by reverse transcription and real-time polymerase chain reaction (RT-PCR). Grip strength was assessed by dynamometry. Oxidative capacity was measured using oleate oxidation rates. Muscle fiber type and size were assessed by histology.
Results
Elevated GH (0.27 ± 0.27 versus 3.6 ± 7.7 ng/ml in HF; p = 0.0002) and lower IGF-1 and insulin-like growth factor binding protein (IGFBP)-3 were found in HF (IGF-1, 144 ± 41 versus 74 ± 45 ng/ml in HF, p < 0.05; and IGFBP-3, 3,880 ± 934 versus 1,935 ± 862 ng/ml in HF, p = 0.05). The GH/IGF-1 ratio, a marker of GH resistance, was elevated in HF (0.002 ± 0.002 versus 0.048 ± 0.1 pre-VAD; p < 0.0039). After VAD support, skeletal muscle expression of IGF-1 and IGFBP-3 increased (10-fold and 5-fold, respectively; p < 0.05) accompanied by enhanced oxidative gene expression (CD36, CPT1, and PGC1α) and increased oxidation rates (+1.37-fold; p < 0.05). Further, VAD implantation increased the oxidative muscle fiber proportion (38 versus 54 %, p = 0.031), fiber cross-sectional area (CSA) (1,005 ± 668 versus 1,240 ± 670 μm2, p < 0.001), and Akt phosphorylation state in skeletal muscle. Finally, hand grip strength increased 26.5 ± 27.5 % at 180 days on-VAD (p < 0.05 versus baseline).
Conclusion
Our data demonstrate that VAD implantation corrects GH/IGF-1 signaling, improves muscle structure and function, and enhances oxidative muscle metabolism in patients with advanced HF.
 
Khawaja T., Chokshi A., Ji R., Kato T.S., Xu K., Zizola C., Wu C., Forman D.E., Ota T., Kennel P., Takayama H.,Naka Y., George I., Mancini D., Schulze C.P., Ventricular assist device implantation improves skeletal muscle function, oxidative capacity, and growth hormone/insulin-like growth factor-1 axis signaling in patients with advanced heart failure. J Cachex Sarcopenia Muscle 2014;4:297-305.

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     Page 307 - 313

David R. Fogelman, Holly Holmes, Khalil Mohammed, Matthew H. G. Katz, Carla M. Prado, Jessica Lieffers, Naveen Garg, Gauri R. Varadhachary, Rachna Shroff, Michael J. Overman, Christopher Garrett, Robert A. Wolff, Milind Javle

Does IGFR1 inhibition result in increased muscle mass loss in patients undergoing treatment for pancreatic cancer?Background
IGF-1 plays a role in the growth of multiple tumor types, including pancreatic cancer. IGF-1 also serves as a growth factor for muscle. The impact of therapeutic targeting of IGF-1 on muscle mass is unknown.
Methods
We evaluated muscle mass at L3 in patients enrolled in a randomized phase II study of MK-0646 (M), a monoclonal antibody directed against the IGF-1 protein, in patients with metastatic pancreatic cancer (MPC). Two different doses of M were tested, 5 and 10 mg/kg. We used the Slice-o-matic (ver 4.3) software to segregate CT images into muscle and fat components and measured muscle area (cm2) at baseline and after 2 and 4 months of treatment. Patients received either gemcitabine with erlotinib (G + E), G + E + M, or G + M. Differences between the groups were compared using t tests.
Results
Fifty-three patients had both baseline and 2-month imaging available for analysis. Of these, 42 received M with their chemo, and 11 had G + E only. After 2 months of treatment, both groups demonstrated decrease in muscle mass. G + E patients lost 5.6 % of muscle mass; M patients lost 9.1 and 8.6 % after treatment with 5 and 10 mg/kg, respectively (p = 0.53). Patients demonstrating a response lost less muscle (median 4.6 %) than those with stable disease (9.6 %) and progressive disease (8.9 %, p = 0.14). Muscle retention from baseline to 2-month imaging, defined as loss of <6 cm2 of muscle, correlated with better survival than those patients demonstrating a muscle loss (HR 0.51, p = 0.03).
Conclusions
MPC patients can be expected to lose muscle mass even while having clinical benefit (PR or SD) from chemotherapy. Muscle loss correlated with a risk of study drop-out and death. There was a non-significant trend toward greater muscle mass loss in patients on anti-IGF-1R therapy. However, it is unclear if this loss translates into functional differences between patients.
 
Fogelman D.R., Holmes H., Mohammed K., Katz M.H.G., Prado C.M., Lieffers J., Garg N., Varadhachary G.R., Shroff R., Overman M.J., Garrett C., Wolff R.A., Javle M., Does IGFR1 inhibition result in increased muscle mass loss in patients undergoing treatment for pancreatic cancer?. J Cachex Sarcopenia Muscle 2014;4:307-313.

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     Page 315 - 320

Míriam Toledo, Jochen Springer, Sílvia Busquets, Anika Tschirner, Francisco J. López-Soriano, Stefan D. Anker, Josep M. Argilés

Formoterol in the treatment of experimental cancer cachexia: effects on heart functionBackground and aims
Formoterol is a highly potent β2-adrenoceptor-selective agonist, which is a muscle growth promoter in many animal species, resulting in skeletal muscle hypertrophy. Previous studies carried out in our laboratory have shown that formoterol treatment in tumour-bearing animals resulted in an amelioration of muscle loss through different mechanisms that include muscle apoptosis and proteolysis.
Methods
The study presented involved rats bearing the Yoshida AH-130 ascites tumour model—which induces a high degree of cachexia—treated with the beta-2 agonist formoterol (0.3 mg/kg BW).
Results
The administration of formoterol to cachectic tumour-bearing rats resulted in a significant reduction of muscle weight loss. The treatment also increased lean body mass and body water. The treatment, however, did not influence heart weight, which was much decreased as a result of tumour burden. Untreated tumour-bearing rats showed important changes in parameters related with heart function:, left ventricle (LV) ejection fraction, fractional shortening, LV diameter and volume (diastolic) and LV stroke volume, LV mass and posterior wall thickness (PWT) (both systolic and diastolic). The administration of formoterol affected LV diameter and volume, LV stroke volume and LV mass.
Conclusions
The results suggest that formoterol treatment, in addition to reducing muscle wasting, does not negatively alter heart function—in fact, some cardiac parameters are improved—in animals affected by cancer cachexia.
 
Toledo M., Springer J., Busquets S., Tschirner A., López-Soriano F.J., Anker S.D., Argilés J.M., Formoterol in the treatment of experimental cancer cachexia: effects on heart function. J Cachex Sarcopenia Muscle 2014;4:315-320.

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     Page 321 - 328

Erin E. Talbert, Gregory A. Metzger, Wei A. He, Denis C. Guttridge

Modeling human cancer cachexia in colon 26 tumor-bearing adult miceBackground
Muscle wasting is a profound side effect of advanced cancer. Cancer-induced cachexia decreases patient quality of life and is associated with poor patient survival. Currently, no clinical therapies exist to treat cancer-induced muscle wasting. Although cancers commonly associated with cachexia occur in older individuals, the standard animal models used to elucidate the causes of cachexia rely on juvenile mice.
Methods
In an effort to better model human cancer cachexia, we determined whether cachectic features seen in young mice could be achieved in adult, pre-sarcopenic mice following colon 26 (C-26) tumor cell inoculation.
Results
Both young and adult mice developed similar-sized tumors and progressed to cachexia with similar kinetics, as evidenced by losses in body mass, and adipose and skeletal muscle tissues. Proteolytic signaling, including proteasome and autophagy genes, was also increased in muscles from both young and adult tumor-bearing animals. Furthermore, tumor-associated muscle damage and activation of Pax7 progenitor cells was induced in both young and adult mice.
Conclusions
Although cancer cachexia generally occurs in older individuals, these data suggest that the phenotype and underlying mechanisms can be effectively modeled using the currently accepted protocol in juvenile mice.
 
Talbert E.E., Metzger G.A., He W.A., Guttridge D.C., Modeling human cancer cachexia in colon 26 tumor-bearing adult mice. J Cachex Sarcopenia Muscle 2014;4:321-328.

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     Page 329 - 337

Claudio Pietra, Yasuhiro Takeda

Anamorelin HCl (ONO-7643), a novel ghrelin receptor agonist, for the treatment of cancer anorexia-cachexia syndrome: preclinical profileBackground
Anamorelin HCl (ANAM) is a novel, orally active, ghrelin receptor agonist in clinical development for the treatment of cancer cachexia. We report in vitro and in vivo studies evaluating the preclinical pharmacologic profile of ANAM.
Methods
Fluorescent imaging plate reader and binding assays in HEK293 and baby hamster kidney cells determined the agonist and antagonist activity of ANAM, and its affinity for the ghrelin receptor. Rat pituitary cells were incubated with ANAM to evaluate its effect on growth hormone (GH) release. In vivo, rats were treated with ANAM 3, 10, or 30 mg/kg, or control orally, once daily for 6 days to evaluate the effect on food intake (FI) and body weight (BW), and once to assess GH response. In pigs, single (3.5 mg/kg) or continuous (1 mg/kg/day) ANAM doses were administered to assess GH and insulin-like growth factor (IGF-1) response.
Results
ANAM showed significant agonist and binding activity on the ghrelin receptor, and stimulated GH release in vitro. In rats, ANAM significantly and dose-dependently increased FI and BW at all dose levels compared with control, and significantly increased GH levels at 10 or 30 mg/kg doses. Increases in GH and IGF-1 levels were observed following ANAM administration in pigs.
Conclusion
ANAM is a potent and highly specific ghrelin receptor agonist with significant appetite-enhancing activity,
leading to increases in FI and BW, and a stimulatory effect on GH secretion. These results support the continued
investigation of ANAM as a potential treatment of cancer anorexia-cachexia syndrome.

Pietra C., Takeda Y., Anamorelin HCl (ONO-7643), a novel ghrelin receptor agonist, for the treatment of cancer anorexia-cachexia syndrome: preclinical profile. J Cachex Sarcopenia Muscle 2014;4:329-337.

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     Page 339 - 345

Kamran A. Mirza, Suzette L. Pereira, Neile K. Edens, Michael J. Tisdale

Attenuation of muscle wasting in murine C2C12 myotubes by epigallocatechin-3-gallateBackground
Loss of muscle protein is a common feature of wasting diseases where currently treatment is limited. This study investigates the potential of epigallocatechin-3-gallate (EGCg), the most abundant catechin in green tea, to reverse the increased protein degradation and rescue the decreased protein synthesis which leads to muscle atrophy.
Methods
Studies were conducted in vitro using murine C2C12 myotubes. Increased protein degradation and reduced rates of protein synthesis were induced by serum starvation and tumour necrosis factor-α (TNF-α).
Results
EGCg effectively attenuated the depression of protein synthesis and increase in protein degradation in murine myotubes at concentrations as low as 10 μM. Serum starvation increased expression of the proteasome 20S and 19S subunits, as well as the proteasome ‘chymotrypsin-like’ enzyme activity, and these were all attenuated down to basal values in the presence of EGCg. Serum starvation did not increase expression of the ubiquitin ligases MuRF1 and MAFbx, but EGCg reduced their expression below basal levels, possibly due to an increased expression of phospho Akt (pAkt) and phospho forkhead box O3a (pFoxO3a). Attenuation of protein degradation by EGCg was increased in the presence of ZnSO4, suggesting an EGCg-Zn2+ complex may be the active species.
Conclusion
The ability of EGCg to attenuate depressed protein synthesis and increase protein degradation in the myotubule model system suggests that it may be effective in preserving skeletal muscle mass in catabolic conditions.
Journal of Cachexia, Sarcopenia and Muscle Journal of Cachexia, Sarcopenia and Muscle
 
Mirza K.A., Pereira S.L., Edens N.K., Tisdale M.J., Attenuation of muscle wasting in murine C2C12 myotubes by epigallocatechin-3-gallate. J Cachex Sarcopenia Muscle 2014;4:339-345.

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     Page 347 - 348

Shailendra Kapoor

 
Kapoor S., Synemin: an evolving role in tumor growth and progression. J Cachex Sarcopenia Muscle 2014;4:347-348.

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     Page 349

Tuba Khawaja, Aalap Chokshi, Ruiping Ji, Tomoko S. Kato, Katherine Xu, Cynthia Zizola, Christina Wu, Daniel E. Forman, Takeyoshi Ota, Peter J. Kennel, Hiroo Takayama,Yoshifumi Naka, Isaac George, Donna Mancini, P. Christian Schulze

 
Khawaja T., Chokshi A., Ji R., Kato T.S., Xu K., Zizola C., Wu C., Forman D.E., Ota T., Kennel P.J., Takayama H.,Naka Y., George I., Mancini D., Schulze P.C., Erratum to: Ventricular assist device implantation improves skeletal muscle function, oxidative capacity, and growth hormone/insulin-like growth factor-1 axis signaling in patients with advanced heart failure. J Cachex Sarcopenia Muscle 2014;4:349.

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