Volume 2 (2011)

Number 1 / March 2011

      Page 1 - 3

Kenneth Fearon, William J. Evans, Stefan D. Anker

Myopenia—a new universal term for muscle wastingA universal term describing the presence of clinically relevant muscle wasting that warrants medical intervention is required. The term sarcopenia might be used in this context. However, common use now means that sarcopenia is more often regarded as synonymous with age-associated muscle wasting in the elderly. We suggest the term “myopenia” to indicate the presence of clinically relevant muscle wasting due to any illness and at any age. This term would translate well into any language and is sufficiently specific if appropriately defined. We suggest to define myopenia as a clinically relevant degree of muscle wasting that is associated either with impaired functional capacity and/or with increased risk of morbidity or mortality. The precise cut-points to define myopenia may be different in various diseases. Myopenia could be diagnosed when a certain degree of muscle wasting over time has occurred (for instance, at least 5% in 6–12 months) or when muscle mass is below a certain threshold level (for instance, the <5th centile of healthy 30-year-olds or a fat-free mass index <16 kg/m2 for men and <15 kg/m2 for women). Future studies need to refine these in a disease-specific manner and link them to degrees of functional impairment that are clinically relevant and/or to degrees of risk of morbid or fatal events.

Scherbakov N, Doehner W. Sarcopenia in stroke-facts and numbers on muscle loss accounting for disability after stroke. J Cachex Sarcopenia Muscle 2011;1:5-8.

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      Page 5 - 8

Nadja Scherbakov,  Wolfram Doehner

Sarcopenia in stroke—facts and numbers on muscle loss accounting for disability after strokeStroke is the third leading cause of death and the leading cause of disability in Western countries. More than 60% of patients remain disabled, 50% of patients suffer from some hemiparesis and 30% remain unable to walk without assistance. The skeletal muscle is the main effector organ accountable for disability in stroke. This disability is, however, traditionally attributed to the brain injury itself and less attention is paid to structural, metabolic and functional aspects of muscle tissue. Hemiparetic stroke leads to various muscle abnormalities. A combination of denervation, disuse, inflammation, remodelling and spasticity account for a complex pattern of muscle tissue phenotype change and atrophy. While the molecular mechanisms of muscle degradation after stroke are only incompletely understood, a stroke-related sarcopenia may be concluded. Reinnervation, fiber-type shift, disuse atrophy and local inflammatory activation are only some of the key features to be addressed. Despite the importance for optimum post stroke recovery, stroke-related sarcopenia is not recognised in current guidelines for stroke therapy and rehabilitation. A total of not more than 500 patients forms the basis for all available evidence on clinical muscle changes after stroke. A lack of robust evidence on muscle pathology after stroke and on treatment strategies becomes apparent that needs to be addressed in an interdisciplinary integrated approach.

Scherbakov N, Doehner W. Sarcopenia in stroke-facts and numbers on muscle loss accounting for disability after stroke. J Cachex Sarcopenia Muscle 2011;1:5-8.

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      Page 9 - 25

Robert H. Mak, Alp T. Ikizler, Csaba P. Kovesdy, Dominic S. Raj, Peter Stenvinkel, et al.

Wasting in chronic kidney diseaseWasting/cachexia is prevalent among patients with chronic kidney disease (CKD). It is to be distinguished from malnutrition, which is defined as the consequence of insufficient food intake or an improper diet. Malnutrition is characterized by hunger, which is an adaptive response, whereas anorexia is prevalent in patients with wasting/cachexia. Energy expenditure decreases as a protective mechanism in malnutrition whereas it remains inappropriately high in cachexia/wasting. In malnutrition, fat mass is preferentially lost and lean body mass and muscle mass is preserved. In cachexia/wasting, muscle is wasted and fat is relatively underutilized. Restoring adequate food intake or altering the composition of the diet reverses malnutrition. Nutrition supplementation does not totally reverse cachexia/wasting. The diagnostic criteria of cachexia/protein–energy wasting in CKD are considered. The association of wasting surrogates, such as serum albumin and prealbumin, with mortality is strong making them robust outcome predictors. At the patient level, longevity has consistently been observed in patients with CKD who have more muscle and/or fat, who report better appetite and who eat more. Although inadequate nutritional intake may contribute to wasting or cachexia, recent evidence indicates that other factors, including systemic inflammation, perturbations of appetite-controlling hormones from reduced renal clearance, aberrant neuropeptide signaling, insulin and insulin-like growth factor resistance, and metabolic acidosis, may be important in the pathogenesis of CKD-associated wasting. A number of novel therapeutic approaches, such as ghrelin agonists and melanocortin receptor antagonists are currently at the experimental level and await confirmation by randomized controlled clinical trials in patients with CKD-associated cachexia/wasting syndrome.Sources of Funding  RHM is supported by National Institutes of Health (NIH), National Institute of Diabetes, Digestive and Kidney Disease (NIDDK) grant U01-DK 03-012, and investigator-initiated grants from the Cystinosis Foundation and Abbott Inc.
TAI is supported by NIH, NIDDK grant K24 DK77875. KKZ is supported by NIH, NIDDK grant R01-DK078106-01, R21-DK078012, and R21-DK077341, and a philanthropist grant from Mr. Harold Simmons.
CPK is supported by NIH, NIDDK grant R01-DK078106-01. CPK is an employee of the US Dept of Veterans Affairs.
DSR is supported by NIH NIDDK grant R01-DK073665-01A1.
PS is supported by the Swedish Medical Research Council.

Mak RH, Ikizler AT, Kovesdy CP, Raj DS, Stenvinkel P, Kalantar-Zadeh K. Wasting in chronic kidney disease. J Cachex Sarcopenia Muscle 2011;1:9-25.

An erratum to this article can be found HERE

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      Page 27 - 35

Lidia Santarpia, Franco Contaldo, Fabrizio Pasanisi

Nutritional screening and early treatment of malnutrition in cancer patientsCachexia affects up to two thirds of all cancer patients and is a significant cause of morbidity and mortality. It is a complex metabolic syndrome associated with the underlying illness and characterized by loss of skeletal muscle tissue with or without loss of fat mass. Cachexia’s other prominent clinical symptoms include anorexia, systemic inflammation, pediatric growth failure, and hypogonadism. The relationship between the symptoms of cancer cachexia and the underlying illness is unclear, and there is an urgent need for a better understanding of the pathophysiology of this syndrome. Normal Zn metabolism is often disrupted in cancer patients, but the possible effects of systemic Zn dyshomeostasis in cachexia have not been investigated. We propose that the acute phase response can mediate Zn redistribution and accumulation in skeletal muscle tissue and contribute to the activation of the ubiquitin–proteasome pathway that regulates protein catabolism. This chronic redistribution deprives Zn from other tissues and organs and compromises critical physiological functions in the body. The cardinal symptoms of Zn deficiency are anorexia, systemic inflammation, growth failure in children, and hypogonadism. These symptoms also prominently characterize cancer cachexia suggesting that the role of systemic Zn dyshomeostasis in cachexia should be investigated.

Santarpia L, Contaldo F, Pasanisi F. Nutritional screening and early treatment of malnutrition in cancer patients. J Cachex Sarcopenia Muscle 2011;1:27-35.

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      Page 37 - 44

Renata Silvério, Alessandro Laviano, Filippo Rossi Fanelli, Marília Seelaender

l-carnitine and cancer cachexia: Clinical and experimental aspectsCancer cachexia is a multifaceted syndrome characterized, among many symptoms, by extensive muscle wasting. Chronic systemic inflammation, partly triggered and sustained by cytokines, as well as increased oxidative stress contributes to the pathogenesis of this complex metabolic disorder. l-carnitine plays a central role in the metabolism of fatty acids and shows important antioxidant and anti-inflammatory properties. Systemic carnitine depletion has been described in several diseases, and it is characterized by fatigue, muscle weakness, and decreased tolerance to metabolic stress. In cachectic cancer patients, low serum carnitine levels have been reported, and this change has been suggested to play an important contributory role in the development of cachexia. Based on these data, carnitine supplementation has been tested in preliminary studies concerning human cachexia, resulting in improved fatigue and quality of life. We present here a review of clinical and experimental evidence regarding the use of carnitine supplementation in the management of cancer cachexia.

Silvério R, Laviano A, Rossi Fanelli F, Seelaender M. l-carnitine and cancer cachexia: Clinical and experimental aspects. J Cachex Sarcopenia Muscle 2011;1:37-44.

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      Page 45 - 56

Fabian Chen, Raymond Lam, David Shaywitz, Ronald C. Hendrickson, Gregory J. Opiteck, et al.

Evaluation of early biomarkers of muscle anabolic response to testosteroneBackground 
Early biomarkers of skeletal muscle anabolism will facilitate the development of therapies for sarcopenia and frailty.
Methods and results 
We examined plasma type III collagen N-terminal propeptide (P3NP), skeletal muscle protein fractional synthesis rate, and gene and protein expression profiles to identify testosterone-induced changes in muscle anabolism. Two placebo-controlled studies enrolled community-dwelling men (study 1, 60–75 years; study 2, 18–40 years) with low to normal testosterone levels. Men were randomized to lower dose (study 1, 100 mg; study 2, 200 mg) or higher dose (study 1, 300 mg; study 2, 600 mg) single intramuscular testosterone or saline injection. After 1 week, testosterone acutely increased plasma P3NP levels in a dose-dependent manner and altered the expression of several skeletal muscle transcripts and proteins. Though not statistically significant, mixed muscle protein fractional synthesis rate tended to increase (1.08-fold with 100 mg testosterone, 1.12-fold with 300 mg testosterone). Testosterone exposure also increased skeletal muscle expression of the collagen type III gene that encodes P3NP.
Conclusion 
P3NP is a potentially useful early biomarker for muscle anabolic therapy. Skeletal muscle protein and RNA profiling are useful tools for the discovery of novel muscle anabolic biomarkers.

Chen F, Lam R, Shaywitz D, Hendrickson RC, Opiteck GJ, Wishengrad D, Liaw A, Song Q, Stewart AJ, Cummings CE, Beals C, Yarasheski KE, Reicin A, Ruddy M, Hu X, Yates NA, Menetski J, Herman GA. Evaluation of early biomarkers of muscle anabolic response to testosterone. J Cachex Sarcopenia Muscle 2011;1:45-56.

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      Page 57 - 62

Míriam Toledo, Sílvia Busquets, Elisabet Ametller, Francisco J. López-Soriano, Josep M. Argilés

Sirtuin 1 in skeletal muscle of cachectic tumour-bearing rats: a role in impaired regeneration?Background: 
In advanced malignant disease, cachexia and muscle wasting appear to be among the most common manifestations. This phenomenon is partially related with a decreased muscle regeneration capacity, as previously described in our laboratory.
Methods and results: 
Rats bearing the Yoshida AH-130 ascites hepatoma were used in the experiments. The animals experienced a marked weight loss with decreases in skeletal muscle weights (13% gastrocnemius, 18% extensor digitorum longus, and 12% tibialis muscles). Muscle gene expression was measured using real-time polymerase chain reaction. Skeletal muscle from cachectic tumour-bearing rats is associated with a decreased expression of genes involved in regeneration such as Pax-7 (39%), myogenin (24%), and MyoD (17%). mRNA levels of Sirt1 increased (91%) in cachectic skeletal muscle. The Sirt1 gene has been shown to be associated with changes in muscle myoblast differentiation. Treatment of the tumour-bearing animals with formoterol—a beta2-agonist—normalizes the expression of genes involved in regeneration (i.e., increase of Pax7 (139%)), at the same time as it does with that of Sirt1 (42% decrease).
Conclusions: 
It is suggested that the lack of muscle regeneration observed during muscle wasting in tumour-bearing animals is linked to the action of Sirt-1, possibly via PGC-1a. These factors may constitute possible targets of pharmacological treatment against muscle loss, thus potentially contributing to the understanding and mitigation of muscle atrophy associated with disease.

Toledo M, Busquets S, Ametller E, López-Soriano FJ, Argilés JM. Sirtuin 1 in skeletal muscle of cachectic tumour-bearing rats: a role in impaired regeneration? J Cachex Sarcopenia Muscle 2011;1:57-62.

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      Page 63 - 69

Thomas Kung, Tibor Szabó, Jochen Springer, Wolfram Doehner, Stefan D. Anker, et al.

Cachexia in heart disease: highlights from the ESC 2010Cardiac cachexia is a co-morbidity that may develop in terminal stages of chronic heart failure (CHF). Up to 15% of ambulatory patients with heart failure are affected. Over the last decades, cardiac cachexia and alterations in muscle metabolism in heart disease have received increasing research interest. This article highlights some recent studies of cardiac cachexia that were presented at the annual meeting of the European Society of Cardiology in September 2010 in Stockholm, Sweden. Studies presented here were focused on effects of exercise training and protein degradation, particularly into the role of the ubiquitin–proteasome complex and its ubiquitin ligases MuRF-1 and MAFbx. Exercise training in patients with CHF was found to increase maximal oxygen consumption and to reduce MuRF-1 expression. Lysosomal muscle degradation does not seem to play a major role in patients with CHF, however, inflammatory cytokines such as tumor necrosis factor-a trigger muscle protein degradation. Other studies found that the serum levels of the adipokine adiponectin are elevated in patients with CHF and that these levels may be correlated with muscle mass, muscle strength in the arms, or with trunk fat mass. Another study showed that the expression of myostatin in skeletal muscle, a negative regulator of muscle growth that is essential for normal regulation of muscle mass, is decreased in spontaneously hypertensive rats with heart failure compared with control animals. This is also true for follistatin, a powerful antagonist, and its potential as a biomarker of muscle wasting. These findings may pave the way for effective treatment approaches to cardiac cachexia.

Kung T, Szabó T, Springer J, Doehner W, Anker SD, von Haehling S. Cachexia in heart disease: highlights from the ESC 2010. J Cachex Sarcopenia Muscle 2011;1:63-69.

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Number 2 / June 2011

      Page 71 - 73

Vickie E. Baracos

Pitfalls in defining and quantifying cachexiaCancer-related symptoms such cachexia and pain are subjects of a proliferation of assessment tools, diagnostic criteria, and systems for staging, which are notably disparate, and lack agreement on the variables to be measured. Teams of experts have worked diligently to develop consensus definitions of the terms cachexia and cancer cachexia, and these efforts provide the basis to develop agreement upon the measurements and tools that are applicable to the diagnosis and staging of cancer cachexia.

Baracos VE. Pitfalls in defining and quantifying cachexia. J Cachex Sarcopenia Muscle 2011;2:71-73.

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      Page 73 - 80

Francesco S. Dioguardi

Clinical use of amino acids as dietary supplement: pros and consNitrogen supply is pivotal for the maintenance of life. Amino acids can be utilized to synthesize both glucose and lipids. The opposite, i.e., production of amino acids from either one of them, is not possible in the absence of other amino acids as donors of nitrogen. The quality of amino acid content in protein has been re-evaluated recently, and the relevance of essential amino acids has been repeatedly underlined. Essential amino acid requirements in different mammals are not identical, and ratios among them should be taken into account when projecting an efficient formulation. Recent research has demonstrated that genes respond to different qualities and quantities of nutritional supply, and increased provision of essential amino acids increases lifespan in animal experiments through mitochondriogenesis and maintenance of elevated rates of synthesis of anti-oxidant molecules. Moreover, genetic expression of key controllers of synthesis, like mTOR, may be particularly important for understanding skeletal muscle maintenance. Losses of muscle mass and impaired immune function are related to reduced protein supply, and there is increasing evidence that regular essential amino acid intake as part of an oral diet is effective in reversing muscle catabolism, promoting muscle anabolism, and restoring immunological function. Therefore, the use of amino acids as supplements to diet would be expanding in the near future. Is this safe? Few data are available on amino acid toxicity, and only one essential amino acid may be considered to have clinically relevant toxicity: methionine, because it is transformed into a toxic intermediate, homocysteine, when cysteine synthesis is required by metabolic needs. Matching of stoichiometric ratios between methionine and cysteine may solve the problem of supplying sufficient amounts of sulfur to the body. Arginine and glutamine are two non-essential amino acids than can become “conditionally essential” because of elevated needs during pathological conditions, and metabolism may not be able to maintain their concentrations at sufficient levels to match metabolic requirements. Chronic exogenous arginine supplementation has not proven to exert positive clinical effects in different trials, and sequential articulation of the knowledge of introduction of arginine-driven transcriptional, translational, and epigenetic adaptations may give us a key for interpreting those puzzling results.

Dioguardi FS. Clinical use of amino acids as dietary supplement: pros and cons. J Cachex Sarcopenia Muscle 2011;2:75-80.

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      Page 81 - 86

Mitja Lainscak, Stephan von Haehling, Wolfram Doehner, Irena Sarc, Tina Jeric, et al.

Body mass index and prognosis in patients hospitalized with acute exacerbation of chronic obstructive pulmonary diseaseBackground  
Nutritional status, weight loss and cachexia have important prognostic implications in patients with chronic obstructive pulmonary disease (COPD). Body mass index (BMI) has been implicated in COPD risk assessment, but information is mostly limited to composite scores or to patients with stable disease. We aimed to analyse the association between BMI and mortality in acute exacerbation of COPD.
Methods  
This retrospective survey included 968 patients hospitalized due to acute exacerbation of COPD at the University Clinic Golnik from February 2002 to June 2007. Vital status was ascertained with Central Population Registry, and database was censored on November 1, 2008.
Results  
Median BMI was 25.08 kg/m2 (interquartile range, 21.55–29.05 kg/m2) and 210 patients (22%) had BMI < 21 kg/m2. During median follow-up of 3.26 years (1.79–4.76 years), 430 patients (44%) died. Lowest mortality was found for BMI 25.09–29.05 kg/m2. When divided per BMI decile, mortality was lowest for BMI 25.09–26.56 kg/m2 (33%). In univariate analysis, BMI per quartile and BMI per unit increase were predictive for all-cause mortality. In an adjusted model, BMI per 1 kg/m2 unit increase was associated with 5% less chance of death (hazard ratio 0.95, 95% confidence interval 0.93–0.97).
Conclusions  
Low BMI < 21 kg/m2 is frequent in patients hospitalized due to acute exacerbation of COPD. Higher BMI was independently predictive of better long-term survival. A better outcome in obese patients compared to normal weight is in contrast to primary prevention data but concurs with observations of an obesity paradox in other cardiovascular diseases.

Lainscak M, von Haehling S, Doehner W, Sarc I, Jeric T, Ziherl K, Kosnik M, Anker SD, Suskovic S. Body mass index and prognosis in patients hospitalized with acute exacerbation of chronic obstructive pulmonary disease. J Cachex Sarcopenia Muscle 2011;2:81-86.

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      Page 87 - 93

Josep M. Argilés, Francisco J. López-Soriano, Míriam Toledo, Angelica Betancourt, Roberto Serpe, et al.

The cachexia score (CASCO): a new tool for staging cachectic cancer patientsBackground  
According to a recent consensus, the cachectic syndrome is defined as: “… a complex metabolic syndrome associated with underlying illness and characterized by loss of muscle with or without loss of fat mass. The prominent clinical feature of cachexia is weight loss in adults (corrected for fluid retention) or growth failure in children (excluding endocrine disorders). Anorexia, inflammation, insulin resistance, and increased muscle protein breakdown are frequently associated with cachexia.” Although this definition is accompanied by diagnostic criteria, it does not consider the problem of staging. Stratification of patients is important when considering therapy. The very first stage of the wasting syndrome does not necessarily involve body weight loss—a state known as pre-cachexia.
Methods and Results  
The aim of the present score was to overcome the problem of patient staging in cancer. This score considers five main different factors: body weight and lean body mass loss; anorexia; inflammatory, immunological, and metabolic disturbances; physical performance; and quality of life. The scoring scale goes from 0 to 100: mild cachexia (less than 25), moderate (more than 26 and less than 50), severe (more than 51 and less than 75), and terminal phase (more than 76 and up to 100). The score also takes into consideration the condition known as pre-cachexia.
Conclusion  
The present score will facilitate cachexia staging and will therefore allow for a more adequate therapy.

Argilés JM, López-Soriano FJ, Toledo M, Betancourt A, Serpe R,  Busquets S. The cachexia score (CASCO): a new tool for staging cachectic cancer patients. J Cachex Sarcopenia Muscle 2011;2:87-93.

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      Page 95 - 104

Fabio Penna, Silvia Busquets, Fabrizio Pin, Miriam Toledo, Francesco M. Baccino, et al.

Combined approach to counteract experimental cancer cachexia: eicosapentaenoic acid and training exerciseBackground  
Cancer cachexia is a syndrome characterized by loss of skeletal muscle protein, depletion of lipid stores, anorexia, weakness, and perturbations of the hormonal homeostasis. Despite several therapeutic approaches described in the past, effective interventions countering cancer cachexia are still lacking.
Methods  
The present work was aimed to verify the ability of eicosapentaenoic acid (EPA) to prevent the muscle depletion in Lewis lung carcinoma-bearing mice and to test the ability of endurance exercise training to increase the EPA effect.
Results  
EPA alone did not prevent the muscle loss induced by tumor growth while the combination with exercise induced a partial rescue of muscle strength and mass. Moreover, the association of EPA and exercise reduced the dramatic PAX-7 accumulation and stimulated the increase of PCG-1 protein.
Conclusions  
Overall, the present data suggest that exercise is an effective tool that should be added for combined therapeutic approaches against cancer cachexia.

Penna F, Busquets S, Pin F, Toledo M, Baccino FM, López-Soriano FJ, Costelli P, Argilés JM. Combined approach to counteract experimental cancer cachexia: eicosapentaenoic acid and training exercise. J Cachex Sarcopenia Muscle 2011;2:95-104.

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      Page 105 - 109

Katja Schmidt, Stephan von Haehling, Wolfram Doehner, Sandra Palus, Stefan D. Anker, et al.

IGF-1 treatment reduces weight loss and improves outcome in a rat model of cancer cachexiaBackground  
A hallmark symptom of cancer cachexia is the loss of skeletal muscle. This is at least partially due to a deregulation of the growth hormone/IGF-1 axis and a subsequently impaired protein synthesis in skeletal muscle. Here, we investigated the effect of IGF-1 supplementation in a rat model of cancer cachexia.
Methods  
Juvenile rats were inoculated with the Yoshida AH-130 hepatoma and treated once daily with 0.3 mg kg−1 day−1 (low dose) or 3 mg kg−1 day−1 (high dose) IGF-1 or placebo for a period of maximal 16 days. Body weight and body composition (by NMR) were assessed at baseline and at the end of the study or day of death. Locomotor activity and food intake were assessed at baseline and day 10/11 after tumour inoculation for 24 h.
Results  
Untreated tumour-bearing rats lost 55.3 ± 2.14 g body weight, which was reduced by low-dose to −39.6 ± 11.1 g (p = 0.0434) and high-dose IGF-1 to −42.7 ± 8.8 g (p = 0.057). Placebo-treated rats lost 41.4 ± 2.0-g lean mass, which was attenuated by low-dose IGF-1 (−28.8 ± 8.3 g, p = 0.041) and high-dose IGF-1 (−30.9 ± 7.4, p = 0.067). Spontaneous activity and food intake were improved by low-dose IGF-1 only. No effect on fat mass was observed. Low-dose IGF-1 significantly reduced mortality (HR = 0.45, 95%CI = 0.21–0.93, p = 0.0315), whilst the high dose did not reach significance (HR = 0.68, 95%CI = 0.26–1.74, p = 0.42).
Conclusion  
Low-dose IGF-1 reduced mortality and attenuated loss of body weight as well as muscle mass in the Yoshida hepatoma rat model. Moreover, an improved quality of life was observed in these animals. Further experiments using different doses are necessary.

Schmidt K, von Haehling S, Doehner W, Palus S, Anker SD, Springer J. IGF-1 treatment reduces weight loss and improves outcome in a rat model of cancer cachexia. J Cachex Sarcopenia Muscle 2011;2:105-109.

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      Page 111 - 117

Nathan A. Stephens, Richard J. E. Skipworth, Alisdair J. MacDonald, Carolyn A. Greig, James A. Ross, et al.

Intramyocellular lipid droplets increase with progression of cachexia in cancer patientsBackground  
Intramyocellular lipids are an important source of fuel for mitochondrial fat oxidation and play an important role in intramuscular lipid homeostasis. We hypothesised that due to the phenotype associated with cancer cachexia, there would exist an association between increasing weight loss and the number/size of intramyocellular lipid droplets.
Methods  
Nineteen cancer patients and 6 controls undergoing surgery were recruited. A rectus abdominis biopsy was performed and processed for transmission electron microscopy (TEM). The number of intramyocellular lipid droplets and lipid droplet diameter were calculated from the TEM images. CT scans, performed as part of patients' routine care, were analysed to determine amount of adipose (intermuscular, visceral and subcutaneous) and muscle tissue.
Results  
Compared with controls, cancer patients had increased numbers of lipid droplets (mean (SD) 1.8 (1.9) vs. 6.4 (9.1) per ×2,650 field, respectively, p = 0.036). Mean (SD) lipid droplet diameter was also higher in cancer patients compared with controls (0.42 (0.13) vs. 0.24 (0.21) μm, p = 0.015). Mean lipid droplet count correlated positively with the severity of weight loss (R = 0.51, p = 0.025) and negatively with CT-derived measures of intermuscular fat (R = −0.53, p = 0.022) and visceral fat (R = −0.51, p = 0.029).
Conclusions  
This study suggests that the number and size of intramyocellular lipid droplets is increased in the presence of cancer and increases further with weight loss/loss of adipose mass in other body compartments.

Stephens NA, Skipworth RJE, MacDonald AJ, Greig CA, Ross JA, Fearon KCH. Intramyocellular lipid droplets increase with progression of cachexia in cancer patients. J Cachex Sarcopenia Muscle 2011;2:111-117.

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      Page 119

Robert H. Mak, T. Alp Ikizler, Csaba P. Kovesdy, Dominic S. Raj, Peter Stenvinkel, et al.

Erratum to: Wasting in chronic kidney disease

Mak RH, Ikizler AT, Kovesdy CP, Raj DS, Stenvinkel P, Kalantar-Zadeh K. Erratum to: Wasting in chronic kidney disease. J Cachex Sarcopenia Muscle 2011;2:119

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Number 3 / September 2011

alt      Page 121 - 123

Thomas Thum, Jochen Springer

Breakthrough in cachexia treatment through a novel selective androgen receptor modulator?!Cachexia, and particularly the loss of metabolically active lean tissue, leads to increased morbidity and mortality in affected patients. An impairment of strength and functional status is usually associated with cachexia. A variety of anabolic and appetite-stimulating agents have been studied in patients with cachexia caused by various underlying diseases. Overall, these studies have demonstrated that treatment can increase body weight and/or lean body mass. However, these therapies may have severe side effects, particularly when utilizing testosterone and related anabolic steroids targeting the androgen receptor. These side effects include cardiovascular problems, prostate hyperplasia and cancer in men, as well as virilization in women.

Thum T, Springer J. Breakthrough in cachexia treatment through a novel selective androgen receptor modulator?! J Cachex Sarcopenia Muscle 2011;3:121-123.

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alt      Page 125 - 134

David Scott, Leigh Blizzard, James Fell, Graeme Jones

The epidemiology of sarcopenia in community living older adults: what role does lifestyle play?Background
Sarcopenia, the age-related decline in skeletal muscle mass and function, is a relatively poorly understood process which may play an important role in the incidence of physical disability and falls in older adults. Evidence demonstrates that both genetic and environmental factors contribute to increased susceptibility for sarcopenia development, yet some of these factors may represent unavoidable consequences of ageing.
Methods
A review of literature, generally from epidemiological research, was performed to examine the influence that potentially modifiable lifestyle factors (general physical activity, dietary nutrient intake and sun exposure), as well as chronic disease and medication use, may have on sarcopenia progression.
Results
The review demonstrated that while physical activity, nutrient intake and sun exposure often decline during ageing, each may have important but differing benefits for the prevention of muscle mass and functional declines in older adults. Conversely, age-related increases in the prevalence of chronic diseases and the subsequent prescription of pharmacotherapy may exacerbate sarcopenia progression.
Conclusions
The prevalence of poor physical activity, diet and sun exposure, as well as chronic disease and medication use, within older adult populations may be modifiable through simple lifestyle and health care interventions. As such, these factors may represent the most effective targets for sarcopenia prevention during the ageing process.

Scott D, Blizzard L, Fell J, Jones G. The epidemiology of sarcopenia in community living older adults: what role does lifestyle play? J Cachex Sarcopenia Muscle 2011;3:125 -134.

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Original Article      Page 135 - 142

Mariantonietta Cicoira, Stefan D. Anker, Claudio Ronco

Cardio-renal cachexia syndromes (CRCS): pathophysiological foundations of a vicious pathological circleCardio-renal syndromes (CRS) are defined as disorders of the heart and kidney whereby acute or chronic dysfunction in one organ may induce acute or chronic dysfunction of the other. CRS have been classified into five categories, where types 2 and 4 represent respectively chronic cardio-renal and chronic reno-cardiac syndromes. In these conditions, the chronic disorder of either the heart or kidney has been shown to induce some degree of cachexia. At the same time, cachexia has been proposed as a possible mechanism contributing to the worsening of such pathological organ cross talk. Common pathogenetic mechanisms underlie body wasting in cachectic states of different chronic heart and kidney diseases. In these circumstances, a vicious circle could arise, in which cachexia associated with either heart failure or chronic kidney disease may contribute to further damage of the other organ. In chronic CRS, activation of the immune and neuroendocrine systems contributes to the genesis of cachexia, which in turn can negatively affect the heart and kidney function. In patients with cardiac sustained activation of the immune and neuroendocrine systems and oxidative stress, renal vascular resistance can increase and therefore impair renal perfusion, leading to worsening kidney function. Similarly, in renal cachexia, increased levels of pro-inflammatory cytokines can cause progressive left ventricular systolic dysfunction, myocardial cell death, endothelial dysfunction and increased myocardial fibrosis, with consequent impairment of the chronic reno-cardiac syndrome type 4. Thus, we speculate that the occurrence of different types of chronic CRS could represent a fundamental step in the genesis of cachexia, being renal and cardiac dysfunction closely related to the occurrence of systemic disorders leading to a final common pathway. Therefore, the heart and kidney and cachexia represent a triad causing a vicious circle that increases mortality and morbidity: In such circumstances, we may plausibly talk about cardio-renal cachexia syndrome. Complex interrelations may explain the transition from CRS to cachexia and from cachexia to CRS. Identification of the exact mechanisms occurring in these conditions could potentially help in preventing and treating this deadly combination.

Cicoira M, Anker SD, Ronco C. Cardio-renal cachexia syndromes (CRCS): pathophysiological foundations of a vicious pathological circle. J Cachex Sarcopenia Muscle 2011;3:135-142.

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alt      Page 143 - 151

Yulia Elkina, Stephan von Haehling, Stefan D. Anker, Jochen Springer

The role of myostatin in muscle wasting: an overviewMyostatin is an extracellular cytokine mostly expressed in skeletal muscles and known to play a crucial role in the negative regulation of muscle mass. Upon the binding to activin type IIB receptor, myostatin can initiate several different signalling cascades resulting in the upregulation of the atrogenes and downregulation of the important for myogenesis genes. Muscle size is regulated via a complex interplay of myostatin signalling with the insulin-like growth factor 1/phosphatidylinositol 3-kinase/Akt pathway responsible for increase in protein synthesis in muscle. Therefore, the regulation of muscle weight is a process in which myostatin plays a central role but the mechanism of its action and signalling cascades are not fully understood. Myostatin upregulation was observed in the pathogenesis of muscle wasting during cachexia associated with different diseases (i.e. cancer, heart failure, HIV). Characterisation of myostatin signalling is therefore a perspective direction in the treatment development for cachexia. The current review covers the present knowledge about myostatin signalling pathways leading to muscle wasting and the state of therapy approaches via the regulation of myostatin and/or its downstream targets in cachexia.

Elkina Y, von Haehling S, Anker SD, Springer J. The role of myostatin in muscle wasting: an overview. J Cachex Sarcopenia Muscle 2011;3:143 -151.

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Original Article      Page 153 - 161

James T. Dalton, Kester G. Barnette, Casey E. Bohl, Michael L. Hancock, Domingo Rodriguez, Shontelle T. Dodson, Ronald A. Morton, Mitchell S. Steiner

The selective androgen receptor modulator GTx-024 (enobosarm) improves lean body mass and physical function in healthy elderly men and postmenopausal women: results of a double-blind, placebo-controlled phase II trialBackground  
Cachexia, also known as muscle wasting, is a complex metabolic condition characterized by loss of skeletal muscle and a decline in physical function. Muscle wasting is associated with cancer, sarcopenia, chronic obstructive pulmonary disease, end-stage renal disease, and other chronic conditions and results in significant morbidity and mortality. GTx-024 (enobosarm) is a nonsteroidal selective androgen receptor modulator (SARM) that has tissue-selective anabolic effects in muscle and bone, while sparing other androgenic tissue related to hair growth in women and prostate effects in men. GTx-024 has demonstrated promising pharmacologic effects in preclinical studies and favorable safety and pharmacokinetic profiles in phase I investigation.
Methods  
A 12-week double-blind, placebo-controlled phase II clinical trial was conducted to evaluate GTx-024 in 120 healthy elderly men (>60 years of age) and postmenopausal women. The primary endpoint was total lean body mass assessed by dual energy X-ray absorptiometry, and secondary endpoints included physical function, body weight, insulin resistance, and safety.
Results  
GTx-024 treatment resulted in dose-dependent increases in total lean body mass that were statistically significant (P < 0.001, 3 mg vs. placebo) and clinically meaningful. There were also significant improvements in physical function (P = 0.013, 3 mg vs. placebo) and insulin resistance (P = 0.013, 3 mg vs. placebo). The incidence of adverse events was similar between treatment groups.
Conclusion  
GTx-024 showed a dose-dependent improvement in total lean body mass and physical function and was well tolerated. GTx-024 may be useful in the prevention and/or treatment of muscle wasting associated with cancer and other chronic diseases.

Dalton JT, Barnette KG, Bohl CE, Hancock ML, Rodriguez D, Dodson ST, Morton RA, Steiner MS. The selective androgen receptor modulator GTx-024 (enobosarm) improves lean body mass and physical function in healthy elderly men and postmenopausal women: results of a double-blind, placebo-controlled phase II trial. J Cachex Sarcopenia Muscle 2011;3:153 -161.

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alt      Page 163 - 174

R. Dallmann, P. Weyermann, C. Anklin, M. Boroff, K. Bray-French, et al.

The orally active melanocortin-4 receptor antagonist BL-6020/979: a promising candidate for the treatment of cancer cachexiaBackground  
Under physiological conditions, the melanocortin system is a crucial part of the complex network regulating food intake and energy expenditure. In pathological states, like cachexia, these two parameters are deregulated, i.e., food intake is decreased and energy expenditure is increased—a vicious combination leading to catabolism. Agouti-related protein (AgRP), the endogenous antagonist at the melanocortin-4 receptor (MC-4R), was found to increase food intake and to reduce energy expenditure. This qualifies MC-4R blockade as an attractive mode of action for the treatment of cachexia. Based on this rationale, a novel series of small-molecule MC-4R antagonists was designed, from which the orally active compound BL-6020/979 (formerly known as SNT207979) emerged as the first promising development candidate showing encouraging pre-clinical efficacy and safety properties which are presented here.
Methods and results  
BL-6020/979 is an orally available, selective and potent MC-4R antagonist with a drug-like profile. It increased food intake and decreased energy expenditure in healthy wild-type but not in MC-4R deficient mice. More importantly, it ameliorated cachexia-like symptoms in the murine C26 adenocarcinoma model; with an effect on body mass and body composition and on the expression of catabolic genes. Moreover, BL-6020/979 showed antidepressant-like properties in the chronic mild stress model in rats and exhibits a favorable safety profile.
Conclusion  
The properties of BL-6020/979 demonstrated in animal models and presented here make it a promising candidate suitable for further development towards a first-in-class treatment option for cachexia that potentially opens up the opportunity to treat two hallmarks of the disease, i.e., decreased food intake and increased energy expenditure, with one drug.

Dallmann R, Weyermann P, Anklin C, Boroff M, Bray-French K, Cardel B, Courdier-Fruh I, Deppe H, Dubach-Powell J, Erb M, Haefeli RH, Henneböhle M, Herzner H, Hufschmid M, Marks DL, Nordhoff S, Papp M, Rummey C, Santos G, Schärer F, Siendt H, Soeberdt M, Sumanovski LT, Terinek M, Mondadori C, Güven N, Feurer A. The orally active melanocortin-4 receptor antagonist BL-6020/979: a promising candidate for the treatment of cancer cachexia. J Cachex Sarcopenia Muscle 2011;3:163-174.

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alt      Page 175 - 180

David W. Russ, Jessica S. Grandy

Increased desmin expression in hindlimb muscles of aging ratsBackground
Aging skeletal muscle frequently exhibits a reduction in force produced per unit muscle tissue, variously termed muscle quality, specific tension or dynapenia. Muscles from animals in which desmin expression is reduced exhibit similar properties, raising the possibility that reduced desmin expression contributes to impaired force production in aging muscles.
Methods
We examined expression of desmin and synemin, both intermediate filament proteins, in the plantarflexor muscles of adult (6–8 months) and older (24 months) rats. We have previously reported age-related reductions in muscle quality and sarcoplasmic reticulum function in these animals.
Results
Significant effects of age and muscle were found for the expression of desmin (P=0.040 and Conclusions
Loss of desmin does not account for reduced force production in aging muscles. The potential effects of the age-related increase in desmin on muscle function remain unclear, but may include dissipation of contractile force.

Russ DW, Grandy JS. Increased desmin expression in hindlimb muscles of aging rats. J Cachex Sarcopenia Muscle 2011;3:175 -180.

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Original Article      Page 181 - 188

Melanie J. Sullivan-Gunn, Siun P. Campbell-O’Sullivan, Michael J. Tisdale, Paul A. Lewandowski

Decreased NADPH oxidase expression and antioxidant activity in cachectic skeletal muscleBackground
Cancer cachexia is the progressive loss of skeletal muscle protein that contributes significantly to cancer morbidity and mortality. Evidence of antioxidant attenuation and the presence of oxidised proteins in patients with cancer cachexia indicate a role for oxidative stress. The level of oxidative stress in tissues is determined by an imbalance between reactive oxygen species production and antioxidant activity. This study aimed to investigate the superoxide generating NADPH oxidase (NOX) enzyme and antioxidant enzyme systems in murine adenocarcinoma tumour-bearing cachectic mice.
Methods
Superoxide levels, mRNA levels of NOX enzyme subunits and the antioxidant enzymes superoxide dismutase (SOD), glutathione peroxidise (GPx) and catalase was measured in the skeletal muscle of mice with cancer and cancer cachexia. Protein expression levels of NOX enzyme subunits and antioxidant enzyme activity was also measured in the same muscle samples.
Results
Superoxide levels increased 1.4-fold in the muscle of mice with cancer cachexia, and this was associated with a decrease in mRNA of NOX enzyme subunits, NOX2, p40phox and p67phox along with the antioxidant enzymes SOD1, SOD2 and GPx. Cancer cachexia was also associated with a 1.3-fold decrease in SOD1 and 2.0-fold decrease in GPx enzyme activity.
Conclusion
Despite increased superoxide levels in cachectic skeletal muscle, NOX enzyme subunits, NOX2, p40phox and p67phox, were downregulated along with the expression and activity of the antioxidant enzymes. Therefore, the increased superoxide levels in cachectic skeletal muscle may be attributed to the reduction in the activity of endogenous antioxidant enzymes.

Sullivan-Gunn MJ, Campbell-O’Sullivan SP, Tisdale MJ, Lewandowski PA. Decreased NADPH oxidase expression and antioxidant activity in cachectic skeletal muscle. J Cachex Sarcopenia Muscle 2011;3:181 -188.

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Number 4 / December 2011

      Page 189 - 190

Stephan von Haehling, Stefan D. Anker

The 6th Cachexia Conference: an introduction to clinical and basic research in an exiting areaNo preview available

Stephan von Haehling, Anker SD The 6th Cachexia Conference: an introduction to clinical and basic research in an exiting area J Cachex Sarcopenia Muscle 2011;4:189-190

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Original Article      Page 191 - 200

Katja Trobec, Stephan von Haehling, Stefan D. Anker, Mitja Lainscak

Growth hormone, insulin-like growth factor 1, and insulin signaling—a pharmacological target in body wasting and cachexiaCachexia is an irreversible process that can develop in the course of chronic disease. It is characterized by the remodeling of the metabolic, inflammatory, and endocrine pathways. Insulin, growth hormone (GH), and insulin-like growth factor 1 (IGF-1) are involved in glucose, protein, and fat metabolism, which regulates body composition. In body wasting and cachexia, their signaling is impaired and causes anabolic/catabolic imbalance. Important mechanisms include inflammatory cytokines and neurohormonal activation. Remodeled post-receptor insulin, GH, and IGF-1 pathways constitute a potential target for pharmacological treatment in the setting of body wasting and cachexia. Peroxisome proliferator-activated receptor gamma agonists, drugs inhibiting angiotensin II action (angiotensin II antagonists and inhibitors of angiotensin-converting enzyme), and testosterone, which interfere with post-receptor pathways of insulin, GH, and IGF-1, were investigated as pharmacological intervention targets and various clinically important implications were reported. There are several other potential targets, but their treatment feasibility and applicability is yet to be established.

Trobec, Katja, von Haehling, Stephan, Anker, Stefan, Lainscak, Mitja Growth hormone, insulin-like growth factor 1, and insulin signaling—a pharmacological target in body wasting and cachexia J Cachex Sarcopenia Muscle 2011;4:191-200

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      Page 201 - 207

Andrew J. Stewart Coats, Venkatesan Srinivasan, Jayaraman Surendran, Haritha Chiramana, Shankar R. K. G. Vangipuram, et al.

The ACT-ONE trial, a multicentre, randomised, double-blind, placebo-controlled, dose-finding study of the anabolic/catabolic transforming agent, MT-102 in subjects with cachexia related to stage III and IV non-small cell lung cancer and colorectal cancer: study designAims  
Cachexia, the wasting disorder associated with a wide range of serious illnesses including cancer, is a major cause of morbidity and mortality. There is currently no widely approved therapeutic agent for treating or preventing cancer-associated cachexia. Colorectal cancer and non-small cell lung cancer have relatively high incidences of cachexia, approximately 28% and 34%, respectively. Neurohormonal overactivity has been implicated in the genesis and progression of cachexia and beta receptor antagonism has been proposed as a potential therapy. MT-102, a novel anabolic/catabolic transforming agent, has a multi-functional effect upon three potential pharmacological targets in cancer cachexia, namely reduced catabolism through non-selective β-blockade, reduced fatigue, and thermogenesis through central 5-HT1a antagonism and increased anabolism through partial β-2 receptor agonism.
Methods  
At least 132 male and female patients, aged between 25 and 80 years with a confirmed diagnosis of late-stage non-small cell lung cancer or colorectal cancer, with cachexia will be randomised to either one of the two MT-102 doses or placebo in a 3:1:2 ratio (MT-102 10 mg BD−1/MT-102 2.5 mg BD/placebo). Patients will continue on study treatment for maximally 16 weeks. The primary endpoint, to be analysed by assigned treatment group, will be body weight change over 16 weeks. For this endpoint, the study has 85% power (0.05% significance level) to detect per 4-week period a mean change of −0.8 kg in the placebo group and 0 kg in the high-dose MT-102 arm. The first patient was randomised in February 2011 and patient recruitment is expected to continue until mid-2012.
Perspective  
The ACT-ONE trial is designed to test whether the anabolic/catabolic transforming agent MT-102 will positively impact on the rate of change of body weight in cancer cachexia, thereby evaluating a novel therapeutic strategy in this hitherto poorly treatable condition. A separate ACT-TWO trial will recruit patients who complete the ACT-ONE trial and remain on randomised double-blind medication. Participants in ACT-TWO will be followed for an additional period with a separate primary endpoint.

Stewart Coats A, Srinivasan V, Surendran J, Chiramana H, Vangipuram S, Bhatt N, Jain M, Shah S, Ali I, Fuang H, Hassan M, Beadle J, Tilson J, Kirwan BA, Anker SD The ACT-ONE trial, a multicentre, randomised, double-blind, placebo-controlled, dose-finding study of the anabolic/catabolic transforming agent, MT-102 in subjects with cachexia related to stage III and IV non-small cell lung cancer and colorectal cancer: study design J Cachex Sarcopenia Muscle 2011;4:201-207

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     Page 209 - 261

Abstracts of the 6th Cachexia Conference, Milan, Italy, December 8–10, 2011No preview available

Abstracts of the 6th Cachexia Conference, Milan, Italy, December 8–10, 2011J Cachex Sarcopenia Muscle 2011;4:209-261

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