Volume 3 (2012)

Number 1 / March 2012

      Page 1 - 4

Mitja Lainscak, Stephan von Haehling, Wolfram Doehner and Stefan D. Anker

The obesity paradox in chronic disease: facts and numbersBody size, particularly large, is a matter of concern among the lay public. Whether this is justified depends upon the state of health and should be judged individually. For patients with established chronic disease, there is sufficient evidence to support the benefits of large body size, i.e., the obesity paradox. This uniform finding is shared over a variety of cardiovascular, pulmonary, and renal diseases and is counterintuitive to the current concepts on ideal body weight. The scientific community has to increase the awareness about differences for optimal body size in health and disease. Simultaneously, clinicians have to be aware about body weight dynamics implications and should interpret the changes in the context of an underlying disease in order to implement the best available management.

Lainscak M., von Haehling S., Doehner W. and Anker S.D. The obesity paradox in chronic disease: facts and numbers. J Cachex Sarcopenia Muscle 2012;1:1-4.

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Original Article      Page 5 - 11

Mary A. Honors and Kimberly P. Kinzig

The role of insulin resistance in the development of muscle wasting during cancer cachexiaBackground
Cancer cachexia is a complex syndrome associated with multiple metabolic abnormalities. Insulin resistance is present in many cancer patients and may be one mechanism through which muscle wasting occurs.
Methods and results
The present review examines evidence in support of a role for insulin resistance in the development of muscle wasting during cancer cachexia and identifies areas for future research. Patients suffering from cancer cachexia tend to exhibit insulin resistance and improvements in insulin resistance have the potential to improve cachexia symptoms. In addition, evidence suggests that insulin resistance may occur prior to the onset of cachexia symptoms.
Conclusions
Further investigation of the role of insulin resistance in cancer cachexia is needed. The use of translational research in this area is strongly encouraged, and has important implications for clinical research and the treatment and prevention of cancer cachexia.

Honors M.A., Kinzig K.P. The role of insulin resistance in the development of muscle wasting during cancer cachexia J Cachex Sarcopenia Muscle 2012;1:5-11.

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Original Article      Page 13 - 23

Elisabetta Ferraro, Francesca Molinari and Libera Berghella

Molecular control of neuromuscular junction developmentSkeletal muscle innervation is a multi-step process leading to the neuromuscular junction (NMJ) apparatus formation. The transmission of the signal from nerve to muscle occurs at the NMJ level. The molecular mechanism that orchestrates the organization and functioning of synapses is highly complex, and it has not been completely elucidated so far. Neuromuscular junctions are assembled on the muscle fibers at very precise locations called end plates (EP). Acetylcholine receptor (AChR) clusterization at the end plates is required for an accurate synaptic transmission. This review will focus on some mechanisms responsible for accomplishing the correct distribution of AChRs at the synapses. Recent evidences support the concept that a dual transcriptional control of AChR genes in subsynaptic and extrasynaptic nuclei is crucial for AChR clusterization. Moreover, new players have been discovered in the agrin–MuSK pathway, the master organizer of postsynaptical differentiation. Mutations in this pathway cause neuromuscular congenital disorders. Alterations of the postynaptic apparatus are also present in physiological conditions characterized by skeletal muscle wasting. Indeed, recent evidences demonstrate how NMJ misfunctioning has a crucial role at the onset of age-associated sarcopenia.

Ferraro E., Molinari F., Berghella L. Molecular control of neuromuscular junction development J Cachex Sarcopenia Muscle 2012;1:13-23.

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     Page 25 - 29

Colin E. Webber and Ronald D. Barr

Age- and gender-dependent values of skeletal muscle mass in healthy children and adolescentsBackground
Skeletal muscle mass (SMM) can be extracted from whole-body scans obtained by X-ray-based dual-photon absorptiometry (DXA). There is a need to establish expected age-dependent values for children and adolescents.
Methods
Appendicular lean tissue mass (ALM) was extracted from whole-body DXA scans in 140 healthy children and adolescents (68 females and 72 males). Whole-body SMM was calculated from ALM using equations developed by Kim et al. (Am J Clin Nutr 84:1014–1020, 2006). Age-dependent patterns of increase in SMM were derived by fitting SMM values to equations that consisted of the sum of two logistic expressions, one accounting for SMM changes during growth and the other for SMM changes during puberty. Normal ranges were defined so that 95% of the SMM values were included.
The reproducibility of SMM measurements was obtained from whole-body DXA scans repeated on three occasions in each of a separate group of 32 normal children with repositioning between scans.
Results
Normal ranges are presented as equations describing the age-dependent pattern of increase in SMM as well as population standard deviations that increased steadily with age. For 15 children below age 10, SMM reproducibility (95% CI) was 149 g (119–199 g) while for 17 children and adolescents over age 10, reproducibility was 170 g (138–223 g).
Conclusion
DXA-based measurements of SMM in children and adolescents are reproducible and can be expressed in terms of age-dependent Z scores.

Webber C.E.,Barr R.D. Age- and gender-dependent values of skeletal muscle mass in healthy children and adolescents  J Cachex Sarcopenia Muscle 2012;1:25-29.

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     Page 31 - 36

Anika Tschirner, Stephan von Haehling, Sandra Palus, Wolfram Doehner, Stefan D. Anke and Jochen Springer

Ursodeoxycholic acid treatment in a rat model of cancer cachexiaBackground
Cancer cachexia is characterized by loss of both adipose and skeletal muscle tissue and by an increased production of proinflammatory cytokines. Ursodeoxycholic acid (UDCA), a bile acid used for centuries in the treatment of liver disease, is known to confer anti-inflammatory and anti-apoptotic effects as well as beneficial effects on mitochondrial integrity and cell signaling. We hypothesized that UDCA ameliorates the wasting process in the Yoshida hepatoma tumor model. In addition, we sought to establish if UDCA exerts beneficial effects on survival in this model.
Methods and results
Forty-seven male rats were inoculated intraperitoneally with 108 Yoshida hepatoma AH-130 cells and treated with placebo or one of two different doses of UDCA, 25 or 100 mg/kg daily. Body weight, body composition, and activity indicators were measured over the course of study up to day 16. UDCA treatment had no effect on tumor growth, loss of body weight, and loss of fat mass. Compared with placebo, low-dose UDCA improved tissue loss in the lung (p = 0.022) and tended to reduce tissue loss in brown adipocytes (p = 0.06), gastrocnemius muscle (p = 0.06), extensor digitorum longus muscle (p = 0.09), and soleus muscle (p = 0.07). Compared with placebo, high-dose UDCA tended to reduce the loss of lean body mass (p = 0.06), lung tissue (p = 0.1), white adipose tissue (p = 0.11), and gastrocnemius muscle (p  = 0.11). The activity and food intake were not altered in tumor-bearing rats by either dose of UDCA. Both doses tended to decrease the mortality rate in tumor-bearing rats, (hazard ratio (HR), 0.42; 95% confidence interval (CI), 0.17–1.04; p = 0.061 for low-dose UDCA; HR, 0.44; 95% CI, 0.18–1.05; p = 0.065 for high-dose UDCA).
Conclusion:
UDCA treatment in the Yoshida hepatoma model showed a trend towards attenuation of tissue loss in animals with progressive weight loss in cancer cachexia. Tumor growth and activity indicators were not altered. Both doses of UDCA tended to reduce the mortality rates in tumor-bearing animals. Larger studies with longer follow-up are required to verify these findings.

Tschirner A., von Haehling S., Palus S., Doehner W., Anker S.D., Springer J. Ursodeoxycholic acid treatment in a rat model of cancer cachexia  J Cachex Sarcopenia Muscle 2012;1:31-36.

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     Page 37 - 43

Sílvia Busquets, Míriam Toledo, Marcel Orpí, David Massa, Maria Porta, Eva Capdevila, Núria Padilla, Valentina Frailis, Francisco J. López-Soriano, H. Q. Han and Josep M. Argilés

Myostatin blockage using actRIIB antagonism in mice bearing the Lewis lung carcinoma results in the improvement of muscle wasting and physical performanceBackground
Cachexia is a multiorganic syndrome associated with cancer, characterized by body weight loss, muscle and adipose tissue wasting and inflammation.
Methods
The aim of this investigation was to examine the effect of the soluble receptor antagonist of myostatin (sActRIIB) in cachectic tumor-bearing animals analyzing
changes in muscle proteolysis and in quality of life.
Results
Administration of sActRIIB resulted in an improvement in body and muscle weights.
Administration of the soluble receptor antagonist of myostatin also resulted in an improvement in the muscle force.
Conclusions
These results suggest that blocking myostatin pathway could be a promising therapeutic strategy for the treatment of cancer cachexia.

Busquets S., Toledo M., Orpí M., Massa D., Porta M., Capdevila E., Padilla N., Frailis V., López-Soriano F.J., Han H. Q., Argilés J.M. Ursodeoxycholic acid treatment in a rat model of cancer cachexia  J Cachex Sarcopenia Muscle 2012;1:37-43.

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     Page 45 - 50

Nicole Ebner, Claudia G. Werner, Wolfram Doehner, Stefan D. Anker and Stephan von Haehling

Recent developments in the treatment of cachexia: highlights from the 6th Cachexia ConferenceWithout Abstract

Ebner N., Werner C.G., Doehner W., Anker S.D., von Haehling S. Recent developments in the treatment of cachexia: highlights from the 6th Cachexia Conference  J Cachex Sarcopenia Muscle 2012;1:45-50.

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     Page 51 - 68

Abstracts of the 6th Cachexia Conference, Milan, Italy, December 8–10, 2011 (Part 2)Without Abstract

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Letter to the Editor     Page 69 - 70

Christopher J. Oliver

Not being able to see the muscle for the fatWithout Abstract

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Letter to the Editor     Page 71 - 70

Nima Alamdari and Per-Olof Hasselgren

Comment on Sirtuin 1 in skeletal muscle of cachectic tumour-bearing ratsWithout Abstract

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Number 2 / June 2012

      Page 73 - 76

Josep M. Argilés, Sílvia Busquets, Francisco J. López-Soriano, Paola Costelli and Fabio Penna

Are there any benefits of exercise training in cancer cachexia?Cancer cachexia is a complex syndrome characterized by inflammation, body weight loss, muscle, and adipose tissue wasting that is responsible for the death of a considerable percentage of cancer patients. In addition, during cachexia muscle strength and endurance are dramatically reduced, limiting the ability to perform daily activities and severely affecting the patient’s quality of life. Different studies have emphasized that a single therapy may not be completely successful in the treatment of cachexia. Beyond pharmacological strategies, exercise training has been suggested as a promising countermeasure to prevent cachexia, in order to restore both strength and endurance, depending on the type of exercise. Unfortunately, a small number of studies, in both clinical and experimental settings, have been performed to date. Moreover, when considering exercise in cancer, several factors have to be taken into consideration, in particular those alterations that could limit the capacity to perform exercise and consequently the resulting beneficial or detrimental effects. This editorial is aimed at stimulating the debate on the suitability of including exercise training in a multi-functional approach against cachexia taking into consideration both limitations and advantages.

Argilés J.M., Busquets S., López-Soriano F.J., Costelli P., Penna F. Are there any benefits of exercise training in cancer cachexia? J Cachex Sarcopenia Muscle 2012;2:73-76.

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Original Article      Page 77 - 94

Mary A. Honors and Kimberly P. Kinzig

Sarcopenia and cachexia: the adaptations of negative regulators of skeletal muscle massRecent advances in our understanding of the biology of muscle, and how anabolic and catabolic stimuli interact to control muscle mass and function, have led to new interest in the pharmacological treatment of muscle wasting. Loss of muscle occurs as a consequence of several chronic diseases (cachexia) as well as normal aging (sarcopenia). Although many negative regulators [Atrogin-1, muscle ring finger-1, nuclear factor-kappaB (NF-κB), myostatin, etc.] have been proposed to enhance protein degradation during both sarcopenia and cachexia, the adaptation of mediators markedly differs among these conditions. Sarcopenic and cachectic muscles have been demonstrated to be abundant in myostatin- and apoptosis-linked molecules. The ubiquitin–proteasome system (UPS) is activated during many different types of cachexia (cancer cachexia, cardiac heart failure, chronic obstructive pulmonary disease), but not many mediators of the UPS change during sarcopenia. NF-κB signaling is activated in cachectic, but not in sarcopenic, muscle. Some studies have indicated a change of autophagic signaling during both sarcopenia and cachexia, but the adaptation remains to be elucidated. This review provides an overview of the adaptive changes in negative regulators of muscle mass in both sarcopenia and cachexia.

Sakuma K., Yamaguchi A. Sarcopenia and cachexia: the adaptations of negative regulators of skeletal muscle mass  J Cachex Sarcopenia Muscle 2012;2:77-94.

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Original Article      Page 95 - 109

David W. Russ, Kimberly Gregg-Cornell, Matthew J. Conaway and Brian C. Clark

Evolving concepts on the age-related changes in “muscle quality”The deterioration of skeletal muscle with advancing age has long been anecdotally recognized and has been of scientific interest for more than 150 years. Over the past several decades, the scientific and medical communities have recognized that skeletal muscle dysfunction (e.g., muscle weakness, poor muscle coordination, etc.) is a debilitating and life-threatening condition in the elderly. For example, the age-associated loss of muscle strength is highly associated with both mortality and physical disability. It is well-accepted that voluntary muscle force production is not solely dependent upon muscle size, but rather results from a combination of neurologic and skeletal muscle factors, and that biologic properties of both of these systems are altered with aging. Accordingly, numerous scientists and clinicians have used the term “muscle quality” to describe the relationship between voluntary muscle strength and muscle size. In this review article, we discuss the age-associated changes in the neuromuscular system—starting at the level of the brain and proceeding down to the subcellular level of individual muscle fibers—that are potentially influential in the etiology of dynapenia (age-related loss of muscle strength and power).

Russ D.W., Gregg-Cornell K., Matthew J., Conaway M.J., Clark B.C.  J Cachex Sarcopenia Muscle 2012;2:95-109.

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     Page 111 - 116

Kristina Norman, Nicole Stobäus, Judith Reiß, Jörg Schulzke, Luzia Valentini and Matthias Pirlich

Effect of sexual dimorphism on muscle strength in cachexiaBackground:
Reduced muscle strength is a cardinal feature in cachexia. We investigated whether weight loss is associated differently with muscle strength in men and women in a large cohort of hospitalized patients.
Methods
One thousand five hundred hospitalized patients (whereof 718 men, mean age 57.6 ± 16.0 years, mean body mass index (BMI) 24.6 ± 4.8 kg/m²) were included in the study. Non-edematous involuntary weight loss was determined with Subjective Global Assessment; isometric maximal muscle strength was evaluated by hand grip strength. Mid-upper arm circumference and triceps skinfold were used to calculate arm muscle area. Interrelationship between sex and weight loss was evaluated by regression analysis performed with the general linear model (GLM) allowing adjustment for continuous and categorical variables and corrected for age, arm muscle area (AMA), BMI, and diagnosis category (benign/malignant disease) as potentially confounding covariates.
Results
Both men and women exhibited a significant stepwise decrease of hand grip strength with increasing weight loss. Age, sex, moderate and severe weight loss, BMI, and AMA were significant predictors of hand grip strength. The GLM moreover revealed a significant sex × weight loss effect, since grip strength was similarly decreased in moderate weight loss in men and women when compared to control patients without weight loss (8.5% in men and 10.5% in women, not significant (n.s.)), but the further reduction of grip strength in severe weight loss was significantly different between men and women (10.6% vs. 4.1%, P = 0.033).
Conclusions
Our findings indicate sex-specific differences in muscle strength response to weight loss.

Norman K.,Stobäus N., Reiß J.,, Schulzke J., Luzia Valentini L, Pirlich M.  J Cachex Sarcopenia Muscle 2012;2:111-116.

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     Page 117 - 137

Melissa J. Puppa, James P. White, Kandy T. Velázquez, Kristen A. Baltgalvis, Shuichi Sato, John W. Baynes and James A. Carson

The effect of exercise on IL-6-induced cachexia in the Apc Min/+ mouseBackground:
Cachexia involves unintentional body weight loss including diminished muscle and adipose tissue mass and is associated with an underlying disease. Systemic overexpression of IL-6 accelerates cachexia in the ApcMin/+ mouse, but does not induce wasting in control C57BL/6 mice. With many chronic diseases, chronic inflammation and metabolic dysfunction can be improved with moderate exercise. A direct effect of regular moderate exercise on the prevention of IL-6-induced cachexia in the ApcMin/+ mouse has not been investigated. The purpose of this study was to assess the effects of exercise on the development of cachexia in the ApcMin/+ mouse. Methods: Mice were randomly assigned to moderate treadmill exercise (18 m/min, 1 h, 6 days/week, 5% grade) or cage control (CC) groups from 6 to 14 weeks of age. At 12 weeks of age, mice were electroporated with either IL-6-containing or control plasmid into the quadriceps muscle. Mice were killed after 2 weeks of systemic IL-6 overexpression or control treatment.
Results:
IL-6 overexpression induced an 8% loss in body weight in CC mice, which was significantly attenuated by exercise. IL-6 overexpression in CC mice increased fasting insulin and triglyceride levels, which were normalized by exercise, and associated with increased oxidative capacity, an induction of AKT signaling, and a repression of AMPK signaling in muscle. These exercise-induced changes occurred despite elevated inflammatory signaling in skeletal muscle.
Conclusion:
We conclude that moderate-intensity exercise can attenuate IL-6-dependent cachexia in ApcMin/+ mice, independent of changes in IL-6 concentration and muscle inflammatory signaling. The exercise effect was associated with improved insulin sensitivity and improved energy status in the muscle.

Puppa M.J., White J.P., Velázquez K.T., Baltgalvis K.A., Sato S., John W. Baynes J.W., Carson J.A.  J Cachex Sarcopenia Muscle 2012;2:117 - 137.

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Letter to the Editor     Page 139

Nancy Schanze and Jochen Springer

Evidence for an effect of ACE inhibitors on cancer cachexiaWihout abstract

Schanze N.,Springer J. Evidence for an effect of ACE inhibitors on cancer cachexia  J Cachex Sarcopenia Muscle 2012;2:139.

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Letter to the Editor     Page 141

Wolfram Doehner

When a reference value makes all the differenceWithout Abstract

Doehner W. J Cachex Sarcopenia Muscle 2012;2:141.

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     Page 143

Erratum to: Recent developments in the treatment of cachexia: highlights from the 6th Cachexia ConferenceWithout Abstract

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Number 3 / September 2012

      Page 145 - 148

Gesine Scharf, Joerg Heineke

Finding good biomarkers for sarcopeniaThe term sarcopenia describes the age-related loss of skeletal muscle mass and function. While this process, in principal, occurs in every adult person and already starts around the age of 40, it is associated with disability, morbidity, and increased mortality in some individuals. In the absence of clear clinical manifestation, we today lack the ability to differentiate between physiological and pathological sarcopenia. In this regard, we need good biomarkers that can be quantified in a reliable, cost-effective manner and that guide diagnosis and therapy of pathological sarcopenia in routine clinical practice and clinical trials. We suggest that a combination of serum markers, diagnostic imaging, and functional tests of muscle function would constitute an ideal biomarker panel. Importantly, sarcopenia biomarkers will have to be tested and validated in clinical trials.

Scharf Gesine, Heineke Joerg, Finding good biomarkers for sarcopenia J Cachex Sarcopenia Muscle 2012;3:145-148

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Original Article      Page 149 - 155

Basil O. Burney, Jose M. Garcia

Hypogonadism in male cancer patientsPrevalence of hypogonadism in men with cancer has been reported between 40% and 90%, which is significantly higher than in the general population. Hypogonadism is likely to affect the quality of life in these patients by contributing to non-specific symptoms, including decreased energy, anorexia, sarcopenia, weight loss, depression, insomnia, fatigue, weakness, and sexual dysfunction. Pathogenesis of hypogonadism in cancer patients is thought to be multi-factorial. Inflammation may play an important role, but leptin, opioids, ghrelin, and high-dose chemotherapy through different mechanisms have all been implicated as the cause. Hypogonadism is also associated with poor survival in cancer patients. Data looking into the treatment of hypogonadal male cancer patients with testosterone are limited. However, improvements in body weight, muscle strength, lean body mass, and quality of life have been shown in hypogonadal men with other chronic diseases on testosterone replacement therapy. Prospective and interventional trials are needed to test the efficacy and safety of testosterone treatment in improving quality of life of these patients.

Burney Basil O., Garcia Jose M., Hypogonadism in male cancer patients J Cachex Sarcopenia Muscle 2012;3:149-155

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Original Article      Page 157 - 162

Prashanth H. Haran, Donato A. Rivas, Roger A. Fielding

Role and potential mechanisms of anabolic resistance in sarcopeniaThere is pressing need to understand the aging process to better cope with its associated physical and societal costs. The age-related muscle wasting known as sarcopenia is a major contributor to the problems faced by the elderly. By hindering mobility and reducing strength, it greatly diminishes independence and quality of life. In studying the factors that contribute to the development of sarcopenia, the focus is shifting to the study of disordered muscle anabolism. The abnormal response of muscle to previously well-established anabolic stimuli is known as anabolic resistance, and may be a key factor in the development and progression of sarcopenia. Factors such as age, obesity, inflammation, and lipotoxicity contribute to anabolic resistance, and have been studied either directly or indirectly in cell systems and whole animals. Understanding the physiologic and mechanistic basis of anabolic resistance could be the key to formulating new and targeted interventions that would ease the burden currently borne by the world’s aged population.

Haran P. H. , Rivas Donato A., Fielding Roger A.  Role and potential mechanisms of anabolic resistance in sarcopenia  J Cachex Sarcopenia Muscle 2012;3:157-162

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Original Article      Page 163 - 179

Alessandro Fanzani, Viviane M. Conraads, Fabio Penna, Wim Martinet

Molecular and cellular mechanisms of skeletal muscle atrophy: an updateSkeletal muscle atrophy is defined as a decrease in muscle mass and it occurs when protein degradation exceeds protein synthesis. Potential triggers of muscle wasting are long-term immobilization, malnutrition, severe burns, aging as well as various serious and often chronic diseases, such as chronic heart failure, obstructive lung disease, renal failure, AIDS, sepsis, immune disorders, cancer, and dystrophies. Interestingly, a cooperation between several pathophysiological factors, including inappropriately adapted anabolic (e.g., growth hormone, insulin-like growth factor 1) and catabolic proteins (e.g., tumor necrosis factor alpha, myostatin), may tip the balance towards muscle-specific protein degradation through activation of the proteasomal and autophagic systems or the apoptotic pathway. Based on the current literature, we present an overview of the molecular and cellular mechanisms that contribute to muscle wasting. We also focus on the multifacetted therapeutic approach that is currently employed to prevent the development of muscle wasting and to counteract its progression. This approach includes adequate nutritional support, implementation of exercise training, and possible pharmacological compounds.

Fanzani A., Conraads V.M., Penna F., Martinet W. Molecular and cellular mechanisms of skeletal muscle atrophy: an update J Cachex Sarcopenia Muscle 2012;3:163-179

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      Page 181 - 190

Matteo Cesari, Roger A. Fielding, Marco Pahor, Bret Goodpaster, Marc Hellerstein, Gabor A. Van Kan, Stefan D. Anker, Seward Rutkove, J. Willem Vrijbloed, Maria Isaac, Yves Rolland, Christine M’Rini, Mylène Aubertin-Leheudre, Jesse M. Cedarbaum, Mauro Zamboni, Cornell C. Sieber, Didier Laurent, William J. Evans, Ronenn Roubenoff, John E. Morley, Bruno Vellas

Biomarkers of sarcopenia in clinical trials—recommendations from the International Working Group on SarcopeniaSarcopenia, the age-related skeletal muscle decline, is associated with relevant clinical and socioeconomic negative outcomes in older persons. The study of this phenomenon and the development of preventive/therapeutic strategies represent public health priorities. The present document reports the results of a recent meeting of the International Working Group on Sarcopenia (a task force consisting of geriatricians and scientists from academia and industry) held on June 7–8, 2011 in Toulouse (France). The meeting was specifically focused at gaining knowledge on the currently available biomarkers (functional, biological, or imaging-related) that could be utilized in clinical trials of sarcopenia and considered the most reliable and promising to evaluate age-related modifications of skeletal muscle. Specific recommendations about the assessment of aging skeletal muscle in older people and the optimal methodological design of studies on sarcopenia were also discussed and finalized. Although the study of skeletal muscle decline is still in a very preliminary phase, the potential great benefits derived from a better understanding and treatment of this condition should encourage research on sarcopenia. However, the reasonable uncertainties (derived from exploring a novel field and the exponential acceleration of scientific progress) require the adoption of a cautious and comprehensive approach to the subject.

Cesari M., Fielding R.A., Pahor M., Goodpaster B., Hellerstein M., Van Kan G.A., Anker S.D., Rutkove S., Vrijbloed J.W., Isaac M., Rolland Y., M’Rini C., Aubertin-Leheudre M., Cedarbaum J.M., Zamboni M., Sieber C.C., Laurent D., Evans W.J. , Roubenoff R., Morley J.E., Vellas B.. Biomarkers of sarcopenia in clinical trials—recommendations from the International Working Group on Sarcopenia. J Cachex Sarcopenia Muscle 2012;3:181-190

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      Page 191 - 198

Tora S. Solheim, Peter M. Fayers, Torill Fladvad, Ben Tan, Frank Skorpen, Kenneth Fearon, Vickie E. Baracos, Pål Klepstad, Florian Strasser, Stein Kaasa and On behalf of the European Palliative Care Research Collaborative (EPCRC) and the European Pharmacogenetic Study (EPOS)

Is there a genetic cause of appetite loss?—an explorative study in 1,853 cancer patientsBackground  
Appetite loss has a major impact on cancer patients. It is exceedingly prevalent, is a prognostic indicator and is associated with inferior quality of life. Cachexia is a multi-factorial syndrome defined by a negative protein and energy balance, driven by a variable combination of reduced food intake and abnormal metabolism. Not all cancer patients that experience weight loss have appetite loss, and the pathophysiology between cachexia and appetite loss may thus be different. Knowledge of pathophysiology of appetite loss in cancer patients is still limited. The primary object of this study was to explore the association with 93 predefined candidate single-nucleotide polymorphisms (SNPs) and appetite loss in cancer patients to possibly generate new theories of the pathophysiology of the condition.
Methods  
A total of 1,853 cancer patients were phenotyped according to appetite loss and then genotyped.
Results  
After allowing for multiple testing, there was no statistically significant association between any of the SNPs analysed and appetite loss. The ten most significant SNPs in the co-dominant model had observed odds ratios varying from 0.72 to 1.28.
Conclusions  
This large exploratory study could not find any associations with loss of appetite and 93 SNPs with a potential to be involved in appetite loss in cancer patients. This does not however rule out genes putative role in the development of the symptom, but the observed odds ratios are close to one which makes it unlikely that any of the individual SNPs explored in the present study have great importance.

Solheim Tora S., Fayers Peter M., Fladvad Torill , Tan Ben, Skorpen Frank , Fearon Kenneth, Baracos Vickie E., Klepstad Pål, Strasser Florian, Kaasa Stein Is there a genetic cause of appetite loss?—an explorative study in 1,853 cancer patients J Cachex Sarcopenia Muscle 2012;3:191-198

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      Page 199 - 211

Felipe E. Pedroso, Paul B. Spalding, Michael C. Cheung, Relin Yang, Juan C. Gutierrez, Andrea Bonetto, Rui Zhan, Ho Lam Chan, Nicholas Namias, Leonidas G. Koniaris and Teresa A. Zimmers

Inflammation, organomegaly, and muscle wasting despite hyperphagia in a mouse model of burn cachexiaBackground  
Burn injury results in a chronic inflammatory, hypermetabolic, and hypercatabolic state persisting long after initial injury and wound healing. Burn survivors experience a profound and prolonged loss of lean body mass, fat mass, and bone mineral density, associated with significant morbidity and reduced quality of life. Understanding the mechanisms responsible is essential for developing therapies. A complete characterization of the pathophysiology of burn cachexia in a reproducible mouse model was lacking.
Methods  
Young adult (12–16 weeks of age) male C57BL/6J mice were given full thickness burns using heated brass plates or sham injury. Food and water intake, organ and muscle weights, and muscle fiber diameters were measured. Body composition was determined by Piximus. Plasma analyte levels were determined by bead array assay.
Results  
Survival and weight loss were dependent upon burn size. The body weight nadir in burned mice was 14 days, at which time we observed reductions in total body mass, lean carcass mass, individual muscle weights, and muscle fiber cross-sectional area. Muscle loss was associated with increased expression of the muscle ubiquitin ligase, MuRF1. Burned mice also exhibited reduced fat mass and bone mineral density, concomitant with increased liver, spleen, and heart mass. Recovery of initial body weight occurred at 35 days; however, burned mice exhibited hyperphagia and polydipsia out to 80 days. Burned mice had significant increases in serum cytokine, chemokine, and acute phase proteins, consistent with findings in human burn subjects.
Conclusions  
This study describes a mouse model that largely mimics human pathophysiology following severe burn injury. These baseline data provide a framework for mouse-based pharmacological and genetic investigation of burn-injury-associated cachexia.

 Pedroso Felipe E.,Spalding Paul B. , Cheung Michael C. , Yang Relin , Gutierrez Juan C. , Bonetto Andrea , Zhan Rui , Chan Ho Lam , Namias Nicholas , Koniaris Leonidas G.,Zimmers Teresa A. Inflammation, organomegaly, and muscle wasting despite hyperphagia in a mouse model of burn cachexia J Cachex Sarcopenia Muscle 2012;3:199-211

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Number 4 / December 2012

            Page 213 - 217

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

From muscle wasting to sarcopenia and myopenia: update 2012Human muscle undergoes constant changes. After about age 50, muscle mass decreases at an annual rate of 1–2 %. Muscle strength declines by 1.5 % between ages 50 and 60 and by 3 % thereafter. The reasons for these changes include denervation of motor units and a net conversion of fast type II muscle fibers into slow type I fibers with resulting loss in muscle power necessary for activities of daily living. In addition, lipids are deposited in the muscle, but these changes do not usually lead to a loss in body weight. Once muscle mass in elderly subjects falls below 2 standard deviations of the mean of a young control cohort and the gait speed falls below 0.8 m/s, a clinical diagnosis of sarcopenia can be reached. Assessment of muscle strength using tests such as the short physical performance battery test, the timed get-up-and-go test, or the stair climb power test may also be helpful in establishing the diagnosis. Serum markers may be useful when sarcopenia presence is suspected and may prompt further investigations. Indeed, sarcopenia is one of the four main reasons for loss of muscle mass. On average, it is estimated that 5–13 % of elderly people aged 60–70 years are affected by sarcopenia. The numbers increase to 11–50 % for those aged 80 or above. Sarcopenia may lead to frailty, but not all patients with sarcopenia are frail—sarcopenia is about twice as common as frailty. Several studies have shown that the risk of falls is significantly elevated in subjects with reduced muscle strength. Treatment of sarcopenia remains challenging, but promising results have been obtained using progressive resistance training, testosterone, estrogens, growth hormone, vitamin D, and angiotensin-converting enzyme inhibitors. Interesting nutritional interventions include high-caloric nutritional supplements and essential amino acids that support muscle fiber synthesis.

von Haehling S., Morley J.E., Anker S.D. , From muscle wasting to sarcopenia and myopenia: update 2012  J Cachex Sarcopenia Muscle 2012;4:213-217

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            Page 219 - 223

Andrew J. S. Coats

Research on cachexia, sarcopenia and skeletal muscle in cardiologyBackground
The awareness of cardiac cachexia, i.e. involuntary weight loss in patients with underlying cardiovascular disease, has increased over the last two decades.
Methods and results
This mini-review looks at recent research in the cardiovascular literature that is relevant to the areas of interest of the Journal of Cachexia, Sarcopenia and Muscle. It identifies significant research in the last 3 years on the obesity paradox, the causes and effects of skeletal muscle wasting, animal models of cachexia and emerging treatment ideas in cardiac cachexia.
Conclusions
Assuming a similar literature in the fields of cancer, chronic obstructive pulmonary disease, chronic renal failure and chronic liver failure, the emergence of cachexia as a vibrant area of clinical and experimental research seems assured.

Coats A.J.S. , Research on cachexia, sarcopenia and skeletal muscle in cardiology  J Cachex Sarcopenia Muscle 2012;4:219-223

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Original Article            Page 225 - 237

Srinivasan Dasarath

Consilience in sarcopenia of cirrhosisCirrhosis is the consequence of progression of many forms of necro-inflammatory disorders of the liver with hepatic fibrosis, hepatocellular dysfunction, and vascular remodeling. Reversing the primary hepatic disorder, liver transplantation, and controlling the complications are the major management goals. Since the former options are not available to the majority of cirrhotics, treating complications remains the mainstay of therapy. Sarcopenia and/or cachexia is the most common complication and adversely affects survival, quality of life, development of other complications of cirrhosis, and outcome after liver transplantation. With the increase in number of cirrhotic patients with hepatitis C and nonalcoholic fatty liver disease, the number of patients waiting for a liver transplantation is likely to continue to increase above the currently estimated 72.3/100,000 population. One of the critical clinical questions is to determine if we can treat sarcopenia of cirrhosis without transplantation. No effective therapies exist to treat sarcopenia because the mechanism(s) of sarcopenia in cirrhosis is as yet unknown. The reasons for this include the predominantly descriptive studies to date and the advances in our understanding of skeletal muscle biology and molecular regulation of atrophy and hypertrophy not being translated into the clinical practice of hepatology. Satellite cell biology, muscle autophagy and apoptosis, and molecular signaling abnormalities in the skeletal muscle of cirrhotics are also not known. Aging of the cirrhotic and transplanted population, use of mTOR inhibitors, and the lack of definitive outcome measures to define sarcopenia and cachexia in this population add to the difficulty in increasing our understanding of hepatic sarcopenia/cachexia and developing treatment options. Recent data on the role of myostatin, AMP kinase, impaired mTOR signaling resulting in anabolic resistance in animal models, and the rapidly developing field of nutriceuticals as signaling molecules need to be evaluated in human cirrhotics. Finally, the benefits of exercise reported in other disease states with sarcopenia may not be safe in cirrhotics due to the risk of gastrointestinal variceal bleeding due to an increase in portal pressure. This article focuses on the problems facing both muscle biologists and hepatologists in developing a comprehensive approach to sarcopenia in cirrhosis.

Dasarath S. , Consilience in sarcopenia of cirrhosis  J Cachex Sarcopenia Muscle 2012;4:225-237

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Original Article            Page 239 - 243

Vicky W. W. Tsai1, Yasmin Husaini, Rakesh Manandhar, K. K. Michelle Lee-Ng, Hong Ping Zhang, Kate Harriott, Lele Jiang, Shu Lin, Amanda Sainsbury, David A. Brown and Samuel N. Breit

Anorexia/cachexia of chronic diseases: a role for the TGF-β family cytokine MIC-1/GDF15Anorexia/cachexia is a common and currently mostly untreatable complication of advanced cancer. It is also a feature of a number of chronic diseases and can also occur as part of the normal ageing process. Over recent years, two different, but sometimes overlapping, processes have been identified to mediate anorexia/cachexia: those that act primarily on muscle reducing its mass and function, and processes that decrease nutrition leading to loss of both fat and muscle. In the case of at least some cancers, the latter process is sometimes driven by marked overexpression of macrophage inhibitory cytokine-1/growth differentiation factor 15 (MIC-1/GDF15). MIC-1/GDF15 is a transforming growth factor beta (TGF-β) family cytokine that is found in the serum of all normal individuals at an average concentration of about 0.6 ng/ml. Its increased expression in both cancers and other diseases can result in 10–100-fold or more elevation of its serum levels. In experimental animals, serum MIC-1/GDF15 levels at the lower end of this range induce anorexia by direct actions of the circulating cytokine on feeding centres in the brain. Mice with tumours overexpressing MIC-1/GDF15 display decreased food intake, loss of lean and fat mass and cachexia. That this process also mediates anorexia/cachexia in humans is suggested by the fact that there is a direct correlation between the degree of serum MIC-1/GDF15 elevation and the amount of cancer-related weight loss, the first such relationship demonstrated. Further, in experimental animals, weight loss can be reversed by neutralisation of tumour-produced MIC-1/GDF15 with a specific monoclonal antibody, suggesting the possibility of effective therapy of patients with the devastating complication of anorexia/cachexia.

Tsai V.W.W., Husaini Y., Manandhar R., Lee-Ng K.K.M., Zhang H.P., Harriott K., Jiang L.,  Lin S., Sainsbury A., Brown D.A. ,Breit S.N., Anorexia/cachexia of chronic diseases: a role for the TGF-β family cytokine MIC-1/GDF15  J Cachex Sarcopenia Muscle 2012;4:239-243

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            Page 245 - 251

Anne E. Utech, Eiriny M. Tadros, Teresa G. Hayes, Jose M. Garcia

Predicting survival in cancer patients: the role of cachexia and hormonal, nutritional and inflammatory markersBackground  
Cancer can lead to weight loss, anorexia, and poor nutritional status, which are associated with decreased survival in cancer patients.
Methods  
Male cancer patients (n = 136) were followed for a mean time of 4.5 years. Variables were obtained at baseline: cancer stage, albumin, hemoglobin, tumor necrosis factor alpha (TNF-α), interleukin (IL)-6, bioavailable testosterone, appetite questionnaire, and weight change from baseline to 18 months. Primary statistical tests included Kaplan–Meier survival analysis and Cox proportional hazard regression (PHREG).
Results  
Univariate PHREG showed that cancer stage, albumin, hemoglobin, TNF-α, IL-6, and weight change were each significantly associated with mortality risk (P < 0.05), but bioavailable testosterone was not. Multivariate PHREG analysis established that weight change and albumin were jointly statistically significant even after adjusting for stage.
Conclusion  
In this sample of male oncology patients, cancer stage, serum albumin, and weight loss predicted survival. High levels of inflammatory markers and hemoglobin are associated with increased mortality, but do not significantly improve the ability to predict survival above and beyond cancer stage, albumin, and weight loss.

Utech A.E., Tadros E.M.,  Hayes T.G., Garcia J.M., Predicting survival in cancer patients: the role of cachexia and hormonal, nutritional and inflammatory markers J Cachex Sarcopenia Muscle 2012;4:245-251

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            Page 253 - 263

Bethan E. Phillips, Kenneth Smith, Sarah Liptrot, Philip J. Atherton, Krishna Varadhan, Michael J. Rennie, Mike Larvin, Jonathan N. Lund, John P. Williams

Cancer cachexia and anabolic interventions: a case reportBackground  
Standard-of-care (SOC) cancer treatments are primarily aimed at reducing size and progression of a tumor. There is a need for successful supplemental anabolic therapies to combat cancer cachexia in addition to these SOC treatment modalities. Anabolic interventions, including testosterone and amino acid supplements, may be beneficial in reducing and/or reversing muscle wasting in these patient populations.
Methods  
A 48-year-old Caucasian female with recurrent cervical cancer was scheduled to receive three 21-day cycles of cisplatin and topetecan chemotherapy. She qualified, consented, and enrolled into a blinded interventional pilot study where she received daily whey protein (10 g, three times per day with meals) and a weekly injection of testosterone enanthate (100 mg intramuscular) before and during the SOC chemotherapy treatment period. Body composition, serum inflammatory markers, mixed muscle protein synthesis and breakdown rates, physical function, fatigue, and quality of life were assessed before and after the intervention period.
Results  
Body composition, as assessed by an increase in body weight and lean body mass and reduction in fat mass; physical function; fatigue; and quality of life each improved across the entire intervention period despite general increases in inflammatory markers and no improvements in muscle protein turnover towards the end of the intervention.
Conclusions  
Concomitant treatment of oral amino acids and testosterone may be a viable therapeutic option for fighting cachexia and improving body composition and quality of life during chemotherapeutic treatment of recurrent cervical cancer. These positive outcomes may be attainable over time despite overall poor inflammatory status.

Phillips B.E., Smith K., Liptrot S., Atherton P.J., Varadhan K., Rennie M.J., Larvin M., Lund, J.N., Williams J.P., Cancer cachexia and anabolic interventions: a case report  J Cachex Sarcopenia Muscle 2012;4:253-263

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            Page 265 - 275

Cloé M. Julienne, Jean-François Dumas, Caroline Goupille, Michelle Pinault, Cécile Berri, Anne Collin, Sophie Tesseraud, Charles Couet, Stephane Servais

Cancer cachexia is associated with a decrease in skeletal muscle mitochondrial oxidative capacities without alteration of ATP production efficiencyBackground  
Cancer cachexia is a complex syndrome related to a negative energy balance resulting in muscle wasting. Implication of muscle mitochondrial bioenergetics alterations during cancer cachexia was suggested. Therefore, the aim of this study was to explore the efficiency of oxidative phosphorylation in skeletal muscle mitochondria in a preclinical model of cancer cachexia.
Methods  
Berlin–Druckrey IX rats with peritoneal carcinosis (PC) were used as a model of cancer cachexia with healthy pair-fed rats (PF) as control. Hindlimb muscle morphology and fibre type composition were analysed in parallel with ubiquitin ligases and UCP gene expression. Oxidative phosphorylation was investigated in isolated muscle mitochondria by measuring oxygen consumption and ATP synthesis rate.
Results  
PC rats underwent significant muscle wasting affecting fast glycolytic muscles due to a reduction in fibre cross-sectional area. MuRF1 and MAFbx gene expression were significantly increased (9- and 3.5-fold, respectively) in the muscle of PC compared to PF rats. Oxygen consumption in non-phosphorylating state and the ATP/O were similar in both groups. Muscle UCP2 gene was overexpressed in PC rats. State III and the uncoupled state were significantly lower in muscle mitochondria from PC rats with a parallel reduction in complex IV activity (−30 %).
Conclusion  
This study demonstrated that there was neither alteration in ATP synthesis efficiency nor mitochondrial uncoupling in skeletal muscle of cachectic rats despite UCP2 gene overexpression. Muscle mitochondrial oxidative capacities were reduced due to a decrease in complex IV activity. This mitochondrial bioenergetics alteration could participate to insulin resistance, lipid droplet accumulation and lactate production

Julienne C.M., Dumas J.F., Goupille C., Pinault M., Berri C., Collin A., Tesseraud S., Couet C., Servais S., Cancer cachexia is associated with a decrease in skeletal muscle mitochondrial oxidative capacities without alteration of ATP production efficiency
J Cachex Sarcopenia Muscle 2012;4:265-275

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Letter to the Editor                                   Page 277 - 278

Shailendra Kapoor

Ursodeoxycholic acid and its emerging role in attenuation of tumor growth in gastrointestinal malignanciesno abstract

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Letter to the Editor                                   Page 279

Anika Tschirner, Jochen Springer

Bile acids for cachexia therapyno abstract

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            Page 281 - 301

 Andrea Bonetto, Chan Ho Lam, Rui Zhan, Felipe E. Pedroso, Leonidas G. Koniaris, Teresa A. Zimmers

Abstracts of the Cancer Cachexia Conference, Boston, USA, 21–23 September 2012no abstract

Bonetto A., Lam C.H., Zhan R., Pedroso F.E., Koniaris L.G., Zimmers T.A. , Abstracts of the Cancer Cachexia Conference, Boston, USA, 21–23 September 2012, J Cachex Sarcopenia Muscle 2012;4:281-301

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