Online First Article

Volume 4 (2013)

Number 1 / March 2013

            Page 1 - 17

Anders Nedergaard, Morten A. Karsdal, Shu Sun, Kim Henriksen

Serological muscle loss biomarkers: an overview of current concepts and future possibilitiesBackground  
The skeletal muscle mass is the largest organ in the healthy body, comprising 30–40 % of the body weight of an adult man. It confers protection from trauma, locomotion, ventilation, and it represents a “sink” in glucose metabolism and a reservoir of amino acids to other tissues such as the brain and blood cells. Naturally, loss of muscle has dire consequences for health as well as functionality. Muscle loss is a natural consequence of especially aging, inactivity, and their associated metabolic dysfunction, but it is strongly accelerated in critical illness such as organ failure, sepsis, or cancer. Whether this muscle loss is considered a primary or secondary condition, it is known that muscle loss is a symptom that predicts morbidity and mortality and one that is known to impact quality of life and independence. Therefore, monitoring of muscle mass is relevant in a number of pathologies as well as in clinical trials as measures of efficacy as well as safety.
Methods and results  
Existing biomarkers of muscle mass or muscle loss have shown to be either too unreliable or too impractical in relation to the perceived clinical benefit to reach regular clinical research or use. We suggest serological neoepitope biomarkers as a possible technology to address some of these problems. Blood biomarkers of this kind have previously been shown to respond with high sensitivity and shorter time to minimum significant change than available biomarkers of muscle mass. We provide brief reviews of existing muscle mass or function biomarker technologies, muscle protein biology, and existing neoepitope biomarkers and proceed to present tentative recommendations on how to select and detect neoepitope biomarkers.
Conclusion  
We suggest that serological peptide biomarkers whose tissue and pathology specificity are derived from post-translational modification of proteins in tissues of interest, presenting so-called neoepitopes, represents an exciting candidate technology to fill out an empty niche in biomarker technology.

Nedergaard A., Karsdal M.A., Sun S., Henriksen K., Serological muscle loss biomarkers: an overview of current concepts and future possibilities  J Cachex Sarcopenia Muscle 2013;1:1-17

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            Page 19 - 29

Sapna S. Patel, Miklos Z. Molnar, John A. Tayek, Joachim H. Ix, Nazanin Noori, Deborah Benner, Steven Heymsfield, Joel D. Kopple, Csaba P. Kovesdy, Kamyar Kalantar-Zadeh

Serum creatinine as a marker of muscle mass in chronic kidney disease: results of a cross-sectional study and review of literatureBackground  
The skeletal muscle mass is the largest organ in the healthy body, comprising 30–40 % of the body weight of an adult man. It confers protection from trauma, locomotion, ventilation, and it represents a “sink” in glucose metabolism and a reservoir of amino acids to other tissues such as the brain and blood cells. Naturally, loss of muscle has dire consequences for health as well as functionality. Muscle loss is a natural consequence of especially aging, inactivity, and their associated metabolic dysfunction, but it is strongly accelerated in critical illness such as organ failure, sepsis, or cancer. Whether this muscle loss is considered a primary or secondary condition, it is known that muscle loss is a symptom that predicts morbidity and mortality and one that is known to impact quality of life and independence. Therefore, monitoring of muscle mass is relevant in a number of pathologies as well as in clinical trials as measures of efficacy as well as safety.
Methods and results  
Existing biomarkers of muscle mass or muscle loss have shown to be either too unreliable or too impractical in relation to the perceived clinical benefit to reach regular clinical research or use. We suggest serological neoepitope biomarkers as a possible technology to address some of these problems. Blood biomarkers of this kind have previously been shown to respond with high sensitivity and shorter time to minimum significant change than available biomarkers of muscle mass. We provide brief reviews of existing muscle mass or function biomarker technologies, muscle protein biology, and existing neoepitope biomarkers and proceed to present tentative recommendations on how to select and detect neoepitope biomarkers.
Conclusion  
We suggest that serological peptide biomarkers whose tissue and pathology specificity are derived from post-translational modification of proteins in tissues of interest, presenting so-called neoepitopes, represents an exciting candidate technology to fill out an empty niche in biomarker technology.

Patel S.S., Molnar N.Z., Tayek J.A., Ix J.H., Noori N., Benner D., Heymsfield S., Kopple J.D., Kovesdy C.P., Kalantar-Zadeh K., Serum creatinine as a marker of muscle mass in chronic kidney disease: results of a cross-sectional study and review of literature J Cachex Sarcopenia Muscle 2013;1:19-29

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Original Article            Page 31 - 39

Lidia Santarpia, Ilenia Grandone, Franco Contaldo, Fabrizio Pasanisi

Butyrylcholinesterase as a prognostic marker: a review of the literatureBackground  
Butyrylcholinesterase (BChE) is an α-glycoprotein synthesized in the liver. Its serum level decreases in many clinical conditions such as acute and chronic liver damage, inflammation, injury and infections, and malnutrition.
Methods and results  
This review collects the main evidence on the emerging role of butyrylcholinesterase as a prognostic marker of liver and nonliver diseases as well as a marker of protein-energy malnutrition and obesity. In fact, serum concentrations and BChE activity seem to accurately reflect the availability of amino acidic substrates and/or derangement in protein synthesis due to hepatocellular damage. In cancer, with or without liver impairment, serum BChE levels serve as an accurate functional and prognostic indicator, useful for monitoring clinical and therapeutic interventions according to patients’ prognosis. In the absence of inflammation, BChE could also serve as an index of the effectiveness of nutritional support.
Conclusions  
Serum BChE assessment should be included in routine clinical diagnostic procedures to evaluate patient clinical conditions, in particular in cases of inflammation and/or protein-energy malnutrition.

Santarpia L., Grandone I., Contaldo F., Pasanisi F., Butyrylcholinesterase as a prognostic marker: a review of the literature J Cachex Sarcopenia Muscle 2013;1:31-39

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            Page 41 - 46

Darren G. Candow, Philip D. Chilibeck, Krissy Weisgarber, Emelie Vogt, Adam D. G. Baxter-Jones

Ingestion of low-dose ibuprofen following resistance exercise in postmenopausal womenBackground  
Postmenopausal women typically experience accelerated muscle loss which has a negative effect on strength. The maximum daily recommended dosage of ibuprofen (1,200 mg) following resistance exercise has been shown to increase muscle hypertrophy and strength in older adults. This study aimed to determine the effects of low-dose ibuprofen (400 mg) immediately following resistance exercise sessions on muscle mass and strength in postmenopausal women.
Methods  
Participants were randomized to ingest ibuprofen (IBU: n = 15, 57.8 ± 5.1 years, 75.9 ± 9.0 kg, 165.9 ± 6.2 cm, BMI = 28 ± 4 kg/m2) or placebo (PLA: n = 13, 56.5 ± 4.4 years, 73.0 ± 10.4 kg, 163.1 ± 5.9 cm, BMI = 26 ± 9 kg/m2) immediately following resistance exercise (11 whole-body exercises), which was performed 3 days/week, on nonconsecutive days, for 9 weeks. Prior to and following training, measures were taken for lean tissue mass (dual-energy X-ray absorptiometry), muscle size of the elbow and knee flexors and extensors and ankle dorsiflexors and plantar flexors (ultrasound), and strength (one-repetition maximum leg press and chest press).
Results  
Over the 9 weeks of training, there were significant changes (p  < 0.05) in lean tissue mass (IBU, −1.1 ± 1.0 kg; PLA, −0.7 ± 1.4 kg), muscle size of the knee extensors (IBU, 0.3 ± 0.6 cm; PLA, 0.2 ± 0.7 cm), ankle dorsiflexors (IBU, 0.5 ± 0.8 cm; PLA, 0.1 ± 0.5 cm), and ankle plantar flexors (IBU, 0.3 ± 0.9 cm; PLA, 0.5 ± 0.9 cm), leg press strength (IBU, 20.6 ± 18.0 kg; PLA, 20.0 ± 20.0 kg), and chest press strength (IBU, 5.1 ± 9.5 kg; PLA, 8.1 ± 7.6 kg), with no differences between groups.
Conclusion  
Low-dose ibuprofen following resistance exercise has no greater effect on muscle mass or strength over exercise alone in postmenopausal women.

Candow D.G., Chilibeck P.D., Weisgarber K., Vogt E., Baxter-Jones A.D.G., Ingestion of low-dose ibuprofen following resistance exercise in postmenopausal women J Cachex Sarcopenia Muscle 2013;1:41-46

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            Page 47 - 54

Bjoern Buehring, Diane Krueger, Neil Binkley

Effect of including historical height and radius BMD measurement on sarco-osteoporosis prevalenceBackground  
A clinical need exists to improve identification of those who will sustain fragility fractures. Individuals with both osteoporosis (OP) and sarcopenia (SP), so-called “sarco-osteoporosis” (SOP), might be at higher fracture risk than those with OP or SP alone. Approaches to facilitate SOP identification, e.g., use of tallest historical rather than current height and inclusion of radius bone mineral density (BMD) measurement, may be of benefit. This study examined the effect of advancing age on SOP prevalence with and without use of historical tallest height and radius BMD measurement.
Methods  
Adults age 60+ underwent dual-energy X-ray absorptiometry (DXA) BMD and total body composition measurement. OP and SP were defined using standard criteria: T-score ≤−2.5 at the lumbar spine or hip and appendicular lean mass (ALM)/current height2 <5.45 kg/m2 (female) and <7.26 kg/m2 (male). Proposed “sensitive” SP criteria used historical tallest height instead of current height, while “sensitive” OP criteria added the 1/3rd radius T-score. The primary outcome was SOP prevalence by decade (60–69, 70–79, 80+).
Results  
A total of 304 individuals (146 M/158 F) participated. OP, SP and SOP prevalence were higher in older adults and increased (p < 0.05) with the “sensitive” criteria. SOP prevalence was lower than that of OP or SP and increased (standard/sensitive) criteria from 1.1 % / 4.5 % in the 60–69 years age group to 10.4 % / 21.9 % in the 80+ years age group.
Conclusions  
SOP prevalence is higher in older adults. Use of historical tallest height and 1/3rd radius BMD increases SOP prevalence. Future studies need to assess whether having SOP increases fracture risk and whether use of tallest height and/or one-third radius BMD improves fracture risk prediction..

 Buehring B., Krueger D., Binkley N., Effect of including historical height and radius BMD measurement on sarco-osteoporosis prevalence J Cachex Sarcopenia Muscle 2013;1:47-54

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            Page 63 - 69

Karsten Lenk, Sandra Palus, Robert Schur, Rakesh Datta, Jesse Dong, Michael D. Culler, Stefan Anker, Jochen Springer, Gerhard Schuler, Volker Adams

Effect of ghrelin and its analogues, BIM-28131 and BIM-28125, on the expression of myostatin in a rat heart failure modelBackground  
In chronic heart failure (CHF), cachexia is a hallmark of the terminal stage of this disease and is associated with a severely reduced quality of life and poor prognosis. Therapeutic options are currently not available. Ghrelin and its analogues BIM-28125 and BIM-28131 (now known as RM-131) have been shown to increase weight in a rat model of CHF. It has been further demonstrated that the expression of myostatin, a negative regulator of skeletal muscle mass, is increased in CHF. The aim of the study was to investigate the influence of ghrelin or its analogues on myostatin in CHF.
Methods  
In an animal model of CHF, Sprague–Dawley rats received either ghrelin or two ghrelin analogues BIM-28125 and BIM-28131 in two different concentrations (50 and 500 nmol/kg/day) compared to placebo. The compounds were delivered using osmotic mini pumps. The expression of myostatin was analyzed in skeletal muscle by RT-PCR and Western blot, and muscle mass of gastrocnemius muscle was measured. The plasma levels of tumor necrosis factor alpha (TNF-α) were measured.
Results  
The relative weight of the gastrocnemius muscle of the sham-operated group was significantly increased compared to placebo-treated CHF rats. The application of ghrelin analogue BIM-28125 and BIM-28131 in their higher concentrations led to a significant reduction in myostatin mRNA expression in comparison to placebo. Myostatin protein expression was significantly reduced in both concentrations of ghrelin and BIM-28131 and in the lower concentration of BIM-28125. The increase of TNF-α plasma concentration in the CHF-animals could be abolished by all used substances.
Conclusions  
In an animal model of CHF, the expression of myostatin is significantly reduced in the skeletal muscle after application of ghrelin and most concentrations of its analogues BIM-28125 and BIM-28131 possibly due to anti-inflammatory effects.

Lenk K., Palus S., Schur, R. Datta R., Dong J., Culler M.D., Anker S.D., Springer J., Schuler G., Adams V. , From muscle wasting to sarcopenia and myopenia: update 2012  J Cachex Sarcopenia Muscle 2013;1:63-69

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            Page 71 - 77

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

Effect of colon cancer and surgical resection on skeletal muscle mitochondrial enzyme activity in colon cancer patients: a pilot studyBackground  
Colon cancer (CC) patients commonly suffer declines in muscle mass and aerobic function. We hypothesised that CC would be associated with reduced muscle mass and mitochondrial enzyme activity and that curative resection would exacerbate these changes.
Methods  
We followed age-matched healthy controls and CC patients without distant metastasis on radiological imaging before and 6 weeks after hemi-colectomy surgery. Body composition was analysed using dual energy X-ray absorptiometry. Mitochondrial enzyme activity and protein concentrations were analysed in vastus lateralis muscle biopsies.
Results  
In pre-surgery, there were no differences in lean mass between CC patients and age-matched controls (46.1 + 32.5 vs. 46.1 + 37.3 kg). Post-resection lean mass was reduced in CC patients (43.8 + 30.3 kg, P < 0.01). When comparing markers of mitochondrial function, the following were observed: pyruvate dehydrogenase (PDH) activity was lower in CC patients pre-surgery (P < 0.001) but normalized post-resection and cytochrome c oxidase and pyruvate dehydrogenase E2 subunit protein expression were lower in CC patients pre-surgery and not restored to control values post-resection (P < 0.001). Nuclear factor kappa-B, an inflammatory marker, was higher in CC patients pre-surgery compared to controls (P < 0.01), returning to control levels post-resection.
Conclusion  
Muscle mass was affected by surgery rather than cancer per se. PDH activity was however lower in cancer patients, suggesting that muscle mass and mitochondrial enzyme activity are not inextricably linked. This reduction in mitochondrial enzyme activity may well contribute to the significant risks of major surgery to which CC patients are exposed.

Phillips B.E., Smith K., Liptrot S., Atherton P. J., Krishna Varadhan K., Rennie M.J., Larvin M., Lund J.N., Williams J.P. J Cachex Sarcopenia Muscle 2013;1:71-77

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            Page 79 - 88

Jean-Christophe Peter, Hélène Rossez, Marjorie Weckering, Géraldine Zipfel, Anne-Catherine Lecourt, Joshua B. Owen, William A. Banks, Karl G. Hofbauer

Protective effects of an anti-melanocortin-4 receptor scFv derivative in lipopolysaccharide-induced cachexia in ratsBackground
Cachexia is a complex syndrome defined by weight loss due to an ongoing loss of skeletal muscle mass with or without loss of body fat. It is often associated with anorexia. Numerous results from experimental studies suggest that blockade of the melanocortin-4 receptor (MC4R) could be an effective treatment for anorexia and cachexia. In a previous study, we reported the basic pharmacological properties of a blocking anti-MC4R mAb 1E8a and its scFv derivative in vitro and in vivo.
Methods  
In the present study, we further characterized the mode of action of the 1E8a scFv, evaluated its pharmacokinetic properties in mice, and assessed its therapeutic potential in a lipopolysaccharide (LPS)-induced cachexia model in rats.
Results  
In vitro, scFv enhanced the efficacy of the endogenous inverse agonist Agouti-related protein. After intravenous (i.v.) administration in mice, the scFv penetrated the blood–brain barrier (BBB) and reached its central sites of action: the scFv brain–serum concentration ratios increased up to 15-fold which suggests an active uptake into brain tissue. In telemetry experiments, i.v. administration of the scFv in rats was well tolerated and only induced slight cardiovascular effects consistent with MC4R blockade, i.e., a small decrease in mean arterial pressure and heart rate. In the model of LPS-induced anorexia, i.v. administration of scFv 1E8a prevented anorexia and loss of body weight. Moreover, it stimulated a myogenic response which may contribute to the preservation of muscle mass in cachexia.
Conclusion  
The pharmacological profile of scFv 1E8a suggests its potential value in the treatment of cachexia or anorexia.

Peter J.C., Rossez H., Weckering M., Zipfel G., Lecourt A.C., Owen J.B., Banks W.A., Hofbauer K.G. Protective effects of an anti-melanocortin-4 receptor scFv derivative in lipopolysaccharide-induced cachexia in rats J Cachex Sarcopenia Muscle 2013;1:79-88

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Number 2 / June 2013

            Page 89 - 94

Kamyar Kalantar-Zadeh, Connie Rhee, John J. Sim, Peter Stenvinkel, Stefan D. Anker, Csaba P. Kovesdy

Why cachexia kills: examining the causality of poor outcomes in wasting conditionsWeight loss is the hallmark of any progressive acute or chronic disease state. In its extreme form of significant lean body mass (including skeletal muscle) and fat loss, it is referred to as cachexia. It has been known for millennia that muscle and fat wasting leads to poor outcomes including death. On one hand, conditions and risk factors that lead to cachexia and inadequate nutrition may independently lead to increased mortality. Additionaly, cachexia per se, withdrawal of nutritional support in progressive cachexia, and advanced age may lead to death via cachexia-specific pathways. Despite the strong and consistent association of cachexia with mortality, no unifying mechanism has yet been suggested as to why wasting conditions are associated with an exceptionally high mortality risk. Hence, the causality of the cachexia–death association, even though it is biologically plausible, is widely unknown. This century-long uncertainty may have played a role as to why the field of cachexia treatment development has not shown major advances over the past decades. We suggest that cachexia-associated relative thrombocytosis and platelet activation may play a causal role in cachexia-related death, while other mechanisms may also contribute including arrhythmia-associated sudden deaths, endocrine disorders such as hypothyroidism, and immune system compromise leading to infectious events and deaths. Multidimensional research including examining biologically plausible models is urgently needed to investigate the causality of the cachexia–death association.

Kalantar-Zadeh K., Rhee C., Sim J.J., Stenvinkel P., Anker S.D., Kovesdy C.P.  Why cachexia kills: examining the causality of poor outcomes in wasting conditions J Cachex Sarcopenia Muscle 2013;2:89-94.

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Original Article            Page 95 - 109

Vanessa C. Vaughan, Peter Martin, Paul A. Lewandowski

Cancer cachexia: impact, mechanisms and emerging treatmentsMany forms of cancer present with a complex metabolic profile characterised by loss of lean body mass known as cancer cachexia. The physical impact of cachexia contributes to decreased patient quality of life, treatment success and survival due to gross alterations in protein metabolism, increased oxidative stress and systemic inflammation. The psychological impact also contributes to decreased quality of life for both patients and their families. Combination therapies that target multiple pathways, such as eicosapentaenoic acid administered in combination with exercise, appetite stimulants, antioxidants or anti-inflammatories, have potential in the treatment of this complex syndrome and require further development

Vaughan V.C., Martin P., Lewandowski P.A.  Cancer cachexia: impact, mechanisms and emerging treatments J Cachex Sarcopenia Muscle 2013;2:95-109.

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Original Article            Page 114 - 124

Douglas W. Gould, Ian Lahart, Amtul R. Carmichael, Yiannis Koutedakis, George S. Metsios

Cancer cachexia prevention via physical exercise: molecular mechanismsCancer cachexia is a debilitating consequence of disease progression, characterised by the significant weight loss through the catabolism of both skeletal muscle and adipose tissue, leading to a reduced mobility and muscle function, fatigue, impaired quality of life and ultimately death occurring with 25–30 % total body weight loss. Degradation of proteins and decreased protein synthesis contributes to catabolism of skeletal muscle, while the loss of adipose tissue results mainly from enhanced lipolysis. These mechanisms appear to be at least, in part, mediated by systemic inflammation. Exercise, by virtue of its anti-inflammatory effect, is shown to be effective at counteracting the muscle catabolism by increasing protein synthesis and reducing protein degradation, thus successfully improving muscle strength, physical function and quality of life in patients with non-cancer-related cachexia. Therefore, by implementing appropriate exercise interventions upon diagnosis and at various stages of treatment, it may be possible to reverse protein degradation, while increasing protein synthesis and lean body mass, thus counteracting the wasting seen in cachexia.

Gould D.W., Lahart I., Carmichael A.R., Koutedakis Y., Metsios G.S. Cancer cachexia prevention via physical exercise: molecular mechanisms J Cachex Sarcopenia Muscle 2013;2:114-124.

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Original Article            Page 125 - 136

Dario Sirabella, Luciana De Angelis, Libera Berghella

Sources for skeletal muscle repair: from satellite cells to reprogrammingSkeletal muscle regeneration is the process that ensures tissue repair after damage by injury or in degenerative diseases such as muscular dystrophy. Satellite cells, the adult skeletal muscle progenitor cells, are commonly considered to be the main cell type involved in skeletal muscle regeneration. Their mechanism of action in this process is extensively characterized. However, evidence accumulated in the last decade suggests that other cell types may participate in skeletal muscle regeneration. Although their actual contribution to muscle formation and regeneration is still not clear; if properly manipulated, these cells may become new suitable and powerful sources for cell therapy of skeletal muscle degenerative diseases. Mesoangioblasts, vessel associated stem/progenitor cells with high proliferative, migratory and myogenic potential, are very good candidates for clinical applications and are already in clinical experimentation. In addition, pluripotent stem cells are very promising sources for regeneration of most tissues, including skeletal muscle. Conditions such as muscle cachexia or aging that severely alter homeostasis may be counteracted by transplantation of donor and/or recruitment and activation of resident muscle stem/progenitor cells. Advantages and limitations of different cell therapy approaches will be discussed.

Sirabella D., De Angelis L., Berghella L. Sources for skeletal muscle repair: from satellite cells to reprogramming J Cachex Sarcopenia Muscle 2013;2:125-136.

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            Page 137 - 144

Sébastien Barbat-Artigas, Stéphanie Plouffe, Charlotte H. Pion, Mylène Aubertin-Leheudre

Toward a sex-specific relationship between muscle strength and appendicular lean body mass index?Background
In spite of some dissociation between muscle mass and strength, muscle strength is often used as a proxy to identify individuals with low muscle mass (sarcopenia). Thus, the aim of the present study was to investigate the relationship between muscle strength and the appendicular lean body mass index (app LBMI).
Methods
One hundred and five individuals were recruited. Knee extension and handgrip strength were measured. Body composition was assessed by DXA. App LBMI was calculated as appendicular lean body mass divided by height squared.
Results
At le level of the entire cohort, both handgrip (r = 0.73; p < 0.001) and knee extension strength (r = 0.57; p < 0.001) were associated with app LBMI. However, in women, knee extension strength (r = 0.32; p < 0.05) but not handgrip strength (r = 0.14; p = 0.35) was associated with app LBMI; while in men, handgrip strength (r = 0.43; p < 0.01) but not knee extension strength (r = 0.27; p = 0.09) was associated with app LBMI.
Conclusions
Muscle strength appears to be associated with lean body mass; however, handgrip strength may be preferentially used in men and knee extension strength in women to detect sarcopenic individuals. Future larger studies are now needed to confirm our findings and their clinical relevance.

Barbat-Artigas S., Plouffe S., Pion C.H.,  Aubertin-Leheudre M. Toward a sex-specific relationship between muscle strength and appendicular lean body mass index? J Cachex Sarcopenia Muscle 2013;2:137-144.

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            Page 145 - 155

Hirak Der-Torossian, Ashley Wysong, Scott Shadfar, Monte S. Willis, Jonathan McDunn, Marion E. Couch

Metabolic derangements in the gastrocnemius and the effect of Compound A therapy in a murine model of cancer cachexiaBackground
Cancer cachexia is a severe wasting syndrome characterized by the progressive loss of lean body mass and systemic inflammation. Inhibiting the signaling of the transcription factor nuclear factor kappa B (NF-κB) largely prevents cancer-induced muscle wasting in murine models. We have previously shown the utility of Compound A, a highly selective novel NF-κB inhibitor that targets the IκB kinase complex, to provide clinical benefit in cancer-induced skeletal muscle and cardiac atrophy.
Methods
Using a metabolomics approach, we describe the changes found between cachectic and noncachectic gastrocnemius muscles before and after Compound A treatment at various doses.
Results
Of the 234 metabolites in the gastrocnemius, cachexia-induced changes in gastrocnemius metabolism reset the steady-state abundances of 42 metabolites (p < 0.05). These changes, not evenly distributed across biochemical categories, are concentrated in amino acids, peptides, carbohydrates and energetics intermediates, and lipids. The gastrocnemius glycolytic pathway is markedly altered—changes consistent with tumor Warburg physiology. This is the first account of a Warburg effect that is not exclusively restricted to cancer cells or rapidly proliferating nonmalignant cells. Cachectic gastrocnemius also displays tricarboxylic acid cycle disruptions, signs of oxidative stress, and impaired redox homeostasis. Compound A only partially rescues the phenotype of the cachectic gastrocnemius, failing to restore the gastrocnemius’ baseline metabolic profile.
Conclusions
The findings in the present manuscript enumerate the metabolic consequences of cachexia in the gastrocnemius and demonstrate that NF-kB targeted treatment only partly rescues the cachectic metabolic phenotype. These data strengthen the previous findings from metabolomic characterization of serum in cachectic animals, suggesting that many of the metabolic alterations observed in the blood originate in the diseased muscle. These findings provide significant insight into the complex pathophysiology of cancer cachexia and provide objective criteria for evaluating future therapeutics.

Der-Torossian H., Wysong A., Shadfar S., Willis M.S., McDunn J., Couch M.E. Metabolic derangements in the gastrocnemius and the effect of Compound A therapy in a murine model of cancer cachexia J Cachex Sarcopenia Muscle 2013;2:145-155.

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            Page 157 - 169

Ian C. Scott, Wendy Tomlinson, Andrew Walding, Beverley Isherwood, Iain G. Dougall

Large-scale isolation of human skeletal muscle satellite cells from post-mortem tissue and development of quantitative assays to evaluate modulators of myogenesisBackground
During aging, there is a decreased ability to maintain skeletal muscle mass and function (sarcopenia). Such changes in skeletal muscle are also co-morbidities of diseases including cancer, congestive heart failure and chronic obstructive pulmonary disease. The loss of muscle mass results in decreased strength and exercise tolerance and reduced ability to perform daily activities. Pharmacological agents addressing these pathologies could have significant clinical impact, but their identification requires understanding of mechanisms driving myotube formation (myogenesis) and atrophy and provision of relevant assays. The aim of this study was to develop robust in vitro methods to study human myogenesis.
Methods
Satellite cells were isolated by digestion of post-mortem skeletal muscle and selection using anti-CD56 MicroBeads. CD56+ cell-derived myotubes were quantified by high content imaging of myosin heavy chains. TaqMan-polymerase chain reaction arrays were used to quantify expression of 41 selected genes during differentiation. The effects of activin receptor agonists and tumour necrosis factor alpha (TNFα) on myogenesis and gene expression were characterised.
Results
Large-scale isolation of CD56+ cells enabled development of a quantitative myogenesis assay with maximal myotube formation 3 days after initiating differentiation. Gene expression analysis demonstrated expression of 19 genes changed substantially during myogenesis. TNFα and activin receptor agonists inhibited myogenesis and downregulated gene expression of muscle transcription factors, structural components and markers of oxidative phenotype, but only TNFα increased expression of pro-inflammatory markers.
Conclusions
We have developed methods for large-scale isolation of satellite cells from muscle and quantitative assays for studying human myogenesis. These systems may prove useful as part of a screening cascade designed to identify therapeutic agents for improving muscle function.

Scott I.C., Tomlinson W., Walding A., Isherwood B., Dougall I.G.. Large-scale isolation of human skeletal muscle satellite cells from post-mortem tissue and development of quantitative assays to evaluate modulators of myogenesis J Cachex Sarcopenia Muscle 2013;2:157-169.

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Number 3 / September 2013

            Page 171

Journal of Cachexia, Sarcopenia and Muscle

An invitation to the 7th Cachexia Conference, Kobe, JapanDear colleagues and friends,
On behalf of the organizing committee, I would like to personally invite you to join us at the 7th Cachexia Conference of the Society on Sarcopenia, Cachexia, and Wasting Disorders from December 9th through December 11th, 2013. This conference will be a great opportunity to meet and discuss in person all issues concerning cachexia, sarcopenia, and body wasting disorders with leading scientists and clinicians from around the world. The program consists of keynote lectures, plenary sessions, both basic and clinical science tracks, and poster presentations. Whether you are a basic science expert or a clinician, or an educator in this field of growing interest, the organizing committee promises you that you will find the program of the 7th Cachexia Conference is worthy of attending.
It is my great pleasure to announce that this year’s event will be held in Kobe, Japan. As you may know, the conference was originally planned to take place in Japan in 2011, however, due to the devastating disaster that had happened earlier in the year, the society had to take a precautious measure to change venues and postpone the opportunity to hold the conference in Japan. Although Kobe is probably known around the world mostly for Kobe Beef, the city can offer much more as it is a historical port where a mixture of Western and Japanese cultures meet. While you are visiting Kobe for the conference, we truly hope that you will take advantage of the opportunity to explore the city as well.
We are looking forward to meeting you at the 7th International Conference of the Society on Sarcopenia, Cachexia, and Wasting Disorders in Kobe, Japan.

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            Page 173 - 178

Jerneja Farkas, Stephan von Haehling, Kamyar Kalantar-Zadeh, John E. Morley, Stefan D. Anker, Mitja Lainscak

Cachexia as a major public health problem: frequent, costly, and deadlyPerception of healthy body size and composition differs considerably across the globe, ethnic groups, cultures, and even inside medical community. Although the concept of ideal body weight has evolved over the past decades, the observation that weight loss can have more deleterious effects within a short-term period than weight gain has remained rather consistent. Weight loss, as a prelude to cachexia, occurs frequently in a variety of disease states and meets the requirements of a global public health problem. Consequently, interventions to prevent and control chronic diseases require a comprehensive approach that targets a population as a whole and includes both prevention and treatment strategies. Around the globe, cachexia awareness campaigns and expanding the current public health priorities to highlight the cachexia magnitude and areas of interventions is necessary. Simultaneously, scientific efforts should provide us with more reliable estimates of body wasting and cachexia as well as pathophysiology of cachexia-associated death. As certain proportion of patients will, irrespective of preventive measures, eventually develop cachexia, a quest for effective remedy remains vital.

Farkas J, von Haehling S., Kalantar-Zadeh K., Morley J.E., Anker S.D., Lainscak M. Cachexia as a major public health problem: frequent, costly, and deadly. J Cachexia Sarcopenia Muscle 2013;3:173-178.

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            Page 179 - 186

Theodore K. Malmstrom, Douglas K. Miller, Margaret M. Herning, John E. Morley

Low appendicular skeletal muscle mass (ASM) with limited mobility and poor health outcomes in middle-aged African AmericansBackground
Recent efforts to provide a consensus definition propose that sarcopenia be considered a clinical syndrome associated with the loss of both skeletal muscle mass and muscle function that occurs with aging. Validation of sarcopenia definitions that include both low muscle mass and poor muscle function is needed.
Methods
In the population-based African American Health (AAH) study (N = 998 at baseline/wave 1), muscle mass and mobility were evaluated in a clinical testing center in a subsample of N = 319 persons (ages 52–68) at wave 4 (2004). Muscle mass was measured using dual energy x-ray absorptiometry and mobility by a 6-min walk test and 4-m gait walk test. Height corrected appendicular skeletal mass (ASM; 9.0 ± 1.5 in n = 124 males, 8.3 ± 2.2 in n = 195 females) was computed as total lean muscle mass in arms and legs (kilograms) divided by the square of height (meters). Cross-sectional and longitudinal (6-year) associations of low ASM (bottom 25 % AAH sample; <7.96 males and <7.06 females) and low ASM with limited mobility (4-m gait walk ≤1 m/s or 6-min walk <400 m) were examined for basic activities of daily living (ADL) difficulties, instrumental activities of daily living (IADL) difficulties, frailty, falls, and mortality (longitudinal only).
Results
Low ASM with limited mobility was associated with IADL difficulties (p = .008) and frailty (p = .040) but not with ADL difficulties or falls in cross-sectional analyses; and with ADL difficulties (p = .022), IADL difficulties (p = .006), frailty (p = .039), and mortality (p = .003) but not with falls in longitudinal analyses adjusted for age and gender. Low ASM alone was marginally associated with mortality (p = .085) but not with other outcomes in cross-sectional or longitudinal analyses.
Conclusion
Low ASM with limited mobility is associated with poor health outcomes among late middle-aged African Americans.

Malmstrom T.K., Miller D.K., Herning M.M., Morley J.E. Low appendicular skeletal muscle mass (ASM) with limited mobility and poor health outcomes in middle-aged African Americans. J Cachexia Sarcopenia Muscle 2013;3:179-186.

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            Page 187 - 197

Michael J. Goodman, Sameer R. Ghate, Panagiotis Mavros, Shuvayu Sen, Robin L. Marcus, Elizabeth Joy, Diana I. Brixner

Development of a practical screening tool to predict low muscle mass using NHANES 1999–2004Background
Skeletal muscle mass declines after the age of 50. Loss of skeletal muscle mass is associated with increased morbidity and mortality.
Objective
This study aims to identify predictors of low skeletal muscle mass in older adults toward development of a practical clinical assessment tool for use by clinicians to identify patients requiring dual-energy X-ray absorptiometry (DXA) screening for muscle mass.
Methods
Data were drawn from the National Health and Nutrition Examination Surveys (NHANES) from 1999 to 2004. Appendicular skeletal mass (ASM) was calculated based on DXA scans. Skeletal muscle mass index (SMI) was defined as the ratio of ASM divided by height in square centimeters. Elderly participants were classified as having low muscle mass if the SMI was 1 standard deviation (SD) below the mean SMI of young adults (20–40 years old). Logistic regression was conducted separately in males and females age ≥65 years of age to examine the relationship between patients identified as having low muscle mass and health behavior characteristics, adjusting for comorbid conditions. The model was validated on a separate sample of 200 patients.
Results
Among the NHANES study population, 551 (39.7 %) males and 374 (27.5 %) females had a SMI below the 1 SD cutoff point. NHANES study subjects with a low SMI were older (mean age, 76.2 vs. 72.7 for male; 76.0 vs. 73.7 for female; and both p < 0.0001) and had a lower body mass index (mean BMI, 24.1 vs. 29.4 for male; 22.9 vs. 29.7 for female; p < 0.0001). In adjusted logistic regression analyses, age (for males) and BMI (for both males and females) remained statistically significant. A parsimonious logistic regression model adjusting for age and BMI only had a C statistic of 0.89 for both males and females. The discriminatory power of the parsimonious model increased to 0.93 for males and 0.95 for females when the cutoff defining low SMI was set to 2 SD below the SMI of young adults. In the validation sample, the sensitivity was 81.6 % for males and 90.6 % for females. The specificity was 66.2 % for males and females.
Conclusions
BMI was strongly associated with a low SMI and may be an informative predictor in the primary care setting. The predictive model worked well in a validation sample.

Goodman M.J., Ghate S.R., Mavros P., Sen S., Marcus R.L., Joy E., Brixner D.I.,  Development of a practical screening tool to predict low muscle mass using NHANES 1999–2004.J Cachexia Sarcopenia Muscle 2013;3:187-197.

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            Page 199 - 207

Michael Knops, Claudia G. Werner, Nadja Scherbakov, Jochen Fiebach, Jens P. Dreier, Andreas Meisel, Peter U. Heuschmann, Gerd J. Jungehülsing, Stephan von Haehling, Ulrich Dirnagl, Stefan D. Anker, Wolfram Doehner

Investigation of changes in body composition, metabolic profile and skeletal muscle functional capacity in ischemic stroke patients: the rationale and design of the Body Size in Stroke Study (BoSSS)Background
Stroke is steadily increasing in prevalence. Muscle tissue wasting and functional changes are frequently observed in stroke, but this has not been studied in detail yet. There is a lack of data to support guideline recommendations on how to target muscle wasting in stroke patients. We hypothesise that pathophysiological metabolic profiles and muscle functional and structural impairment are developing in stroke patients, which are associated with stroke severity and outcome after stroke.
Methods
The Body Size in Stroke Study (BoSSS) is a prospective, longitudinal observation study that will explore associations between the metabolic profile, body tissue wasting and particular metabolic and functional changes in skeletal muscle tissue in stroke patients. Consecutive patients with acute stroke (n = 150) will be enrolled due to lacunar or territorial ischemic infarct in the area of the middle cerebral artery. Patients will be studied at annual intervals after 12 and 24 months. For comparison, healthy controls of similar age and patients with chronic heart failure will be used as control groups. The main objective is to study changes in body composition in stroke patients. Secondary, the study will focus on changes in insulin sensitivity of adipose tissue and skeletal muscle. Furthermore, measurements of endothelial function and peripheral blood flow will provide insight in the vascular regulation in stroke patients.
Conclusion
This study will be the largest observational study providing insights into the metabolic and functional changes of muscle tissue in patients with acute ischemic stroke. The new data will increase our understanding of the pathophysiologic tissue wasting in stroke disease and help to develop new therapeutic strategies.

Knops M., Werner C.G., Scherbakov N.,Fiebach J., Dreier J.P., Meisel A., Heuschmann P.U., Jungehülsing G.J., von Haehling S., Dirnagl U., Anker S.D., Doehner W.,  Investigation of changes in body composition, metabolic profile and skeletal muscle functional capacity in ischemic stroke patients: the rationale and design of the Body Size in Stroke Study (BoSSS) J Cachexia Sarcopenia Muscle 2013;3:199-207.

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            Page 209 - 216

Anthony M. Villani, Michelle D. Miller, Ian D. Cameron, Susan Kurrle, Craig Whitehead, Maria Crotty

Development and relative validity of a new field instrument for detection of geriatric cachexia: preliminary analysis in hip fracture patientsBackground
Geriatric cachexia is distinct from other age-related muscle wasting syndromes; however, detection and therefore treatment is challenging without the availability of valid instruments suitable for application in the clinical setting. This study assessed the sensitivity and specificity of a newly developed screening instrument utilising portable assessments against previously defined and commonly accepted diagnostic criteria for detection of geriatric cachexia.
Methods
Cross-sectional analyses from 71 older adults’ post-surgical fixation for hip fracture were performed. The diagnostic criteria required measures of appendicular skeletal muscle index derived from dual-energy X-ray absorptiometry and anorexia assessed by ≤70 % of estimated energy requirements. These assessments were replaced with mid-upper arm muscle circumference and the Simplified Nutritional Appetite Questionnaire, respectively, to create a field instrument suitable for screening geriatric cachexia. Sensitivity, specificity and positive and negative predictive values were calculated.
Results
The current diagnostic algorithm identified few patients as cachectic (4/71; 5.6 %). The sensitivity and specificity of the geriatric cachexia screening tool was 75 and 97 %, respectively. The screening tool had a positive predictive value of 60 % and a negative predictive value of 99 %.
Conclusions
Given the unexpected prevalence of cachexia in such a vulnerable group, these results may suggest problems in operationalising of the consensus definition and diagnostic criteria. Although the application of a newly developed screening tool using portable field measures looks promising, the authors recommend additional research to identify the prevalence of geriatric cachexia, which captures all diagnostic criteria from the consensus definition. Future investigation may then be positioned to explore the predictive validity of screening tools using portable field measures, which potentially achieve higher sensitivity.

Villani A.M., Miller M.D., Cameron I.D.,Kurrle S., Whitehead C., Crotty M.,Development and relative validity of a new field instrument for detection of geriatric cachexia: preliminary analysis in hip fracture patients. J Cachexia Sarcopenia Muscle 2013;3:209-216.

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            Page 217 - 223

Stephen A. Stimpson, Michael S. Leonard, Lisa G. Clifton, James C. Poole, Scott M. Turner, Todd W. Shearer, Katja S. Remlinger, Richard V. Clark, Marc K. Hellerstein, William J. Evans

Longitudinal changes in total body creatine pool size and skeletal muscle mass using the D3-creatine dilution methodBackground
We recently validated in cross-sectional studies a new method to determine total body creatine pool size and skeletal muscle mass based on D3-creatine dilution from an oral dose and detection of urinary creatinine enrichment by isotope ratio mass spectrometry (IRMS). Routine clinical use of the method in aging and disease will require repeated application of the method, with a more widely available technology than IRMS, to enable determination of change in skeletal muscle mass in longitudinal studies. We therefore adapted the method to liquid chromatography-tandem mass spectrometry (LC-MS/MS) technology, and sought to establish proof of concept for the repeated application of the method in a longitudinal study. Because the turnover of creatine is slow, it was also critical to determine the impact of background enrichment from an initial dose of oral D3-creatine on subsequent, longitudinal measurements of change in muscle mass.
Methods
Rats were given an oral tracer dose of D3-creatine (1.0 mg/kg body weight) at 10 and 17 weeks of age. LC-MS/MS was used to determine urinary D3-creatine, and urinary D3-creatinine enrichment, at time intervals after D3-creatine administration. Total body creatine pool size was calculated from urinary D3-creatinine enrichment at isotopic steady state 72 h after administration of D3-creatine tracer.
Results
At 10 weeks of age, rat lean body mass (LBM) measured by quantitative magnetic resonance correlated with creatine pool size (r = 0.92, P = 0.0002). Over the next 7 weeks, the decline in urinary D3-creatinine enrichment was slow and linear, with a rate constant of 2.73 ± 0.06 %/day. Subtracting background urinary D3-creatinine enrichment from the elevated enrichment following a second dose of D3-creatine at 17 weeks permitted repeat calculations of creatine pool size. As at 10 weeks, 17-week LBM correlated with creatine pool size (r = 0.98, P <0.0001). In addition, the change in creatine pool size was correlated with the change in LBM during the 7 weeks of rat growth between measurements (r = 0.96, P <0.0001).
Conclusion
The LC-MS/MS-based D3-creatine dilution method can be applied repeatedly to measure total body creatine skeletal muscle mass change in longitudinal study.

Stimpson S.A., Leonard M.S., Clifton L.G., Poole J.C., Turner S.M., Shearer T.W., Remlinger K.S., Clark R.V., Hellerstein M.K., Evans W.J., Longitudinal changes in total body creatine pool size and skeletal muscle mass using the D3-creatine dilution method. J Cachexia Sarcopenia Muscle 2013;3:217-223.

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            Page 225 - 229

Gabor Abellan van Kan, Matteo Cesari, Sophie Gillette-Guyonnet, Charlotte Dupuy, Bruno Vellas, Yves Rolland

Association of a 7-year percent change in fat mass and muscle mass with subsequent cognitive dysfunction: the EPIDOS-Toulouse cohortBackground
Cognitive dysfunction and changes in body composition share common pathophysiological pathways. The aim of the present paper was to evaluate whether changes in appendicular muscle mass (AMM) and fat mass (FM) are associated factors with an increased risk of cognitive dysfunction in community-dwelling older women.
Methods
A nested case–control study was performed in 181 women aged 75 years and older from a subsample of the Epidemiologie de l'Osteoporose participants from Toulouse. Body composition parameters at inclusion and 7 years later (assessed by dual energy X-ray absorptiometry), and the presence of cognitive dysfunction (dementia and mild cognitive impairment) at 7 years of follow-up, assured by two memory experts based on best clinical practice and validated criteria, were obtained. Multivariate logistic regression models assessed the association of percent change in AMM and FM with risk of cognitive dysfunction.
Results
At 7 years of follow-up, 15 participants suffered from dementia, 6 suffered from mild cognitive impairment, and 160 were cognitively normal. Neither body composition changes nor gait speed was found to be statistically associated with cognitive dysfunction after controlling for potential confounders. Only age, over 85 years, was associated with an increased risk of subsequent cognitive impairment (odds ratio 3.10; 95 % confidence interval 1.07–8.87).
Conclusions
No significant association could be evidenced between changes in body composition and cognitive dysfunction. Due to the small sample size, statistical power could be an issue. The study could also suggest the possibility that the risk of cognitive dysfunction is not mediated by changes in body composition.

van Kan G.A., Cesari M., Gillette-Guyonnet S., Dupuy C., Vellas B., Rolland Y., Association of a 7-year percent change in fat mass and muscle mass with subsequent cognitive dysfunction: the EPIDOS-Toulouse cohort. J Cachexia Sarcopenia Muscle 2013;3:225-229.

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            Page 231 - 238

Lidiane I. Filippin, Vivian N. Teixeira, Paula R. Viacava, Priscila S. Lora, Laura L. Xavier, Ricardo M. Xavier

Temporal development of muscle atrophy in murine model of arthritis is related to disease severityBackground
Rheumatoid arthritis (RA) is an inflammatory autoimmune disease of unknown etiology, affecting mainly the joint but also other tissues. RA patients usually present weakness and muscle atrophy, nonarticular manifestations of the disease. Although causing great impact, the understanding of muscle atrophy, its development, and the mechanisms involved is still very limited. The objective of this study is to evaluate the development of muscle atrophy in skeletal muscle of a murine model of arthritis.
Methods
The experimental murine model of collagen-induced arthritis (CIA) was used. DBA/1J mice were randomly divided into three groups: control (CO, n = 25), sham arthritis (SA, n = 25), and arthritis (CIA, n = 28), analyzed in different time points: 25, 35, and 45 days after the induction of arthritis. The arthritis development was followed by clinical scores and hind paw edema three times a week. The spontaneous exploratory locomotion and weight were evaluated weekly. In all time points, serum was collected before the death of the animals for cytokine analysis, and myofiber cross-sectional areas (CSA) of gastrocnemius (GA) and tibialis anterior (TA) skeletal muscles were evaluated.
Results
The clinical parameters of arthritis progressively increased in CIA in all experimental times, demonstrating the greatest difference from other groups at 45 days after induction (clinical score: CO, 00 ± 00; SA, 1.00 ± 0.14; CIA, 3.28 ± 0.41 p > 0.05). The CIA animals had lower weights during all the experimentation periods with a difference of 6 % from CO at 45 days (p > 0.05). CIA animals also demonstrated progressive decrease in distance walked, with a reduction of 54 % in 35 and 74 % at 45 days. Cytokine analysis identified significant increase in IL-6 serum levels in CIA than CO and SA in all experimental times. CSA of the myofiber of GA and TA was decreased 26 and 31 % (p > 0.05) in CIA in 45 days after the induction of disease, respectively. There was significant and inverse correlation between the disease clinical score and myofiber CSA in 45 days (GA: r = −0.71; p = 0.021).
Conclusion
Our results point to a progressive development of muscle wasting, with premature onset arthritis. These observations are relevant to understand the development of muscle loss, as well as for the design of future studies trying to understand the mechanisms involved in muscle wasting. As far as we are concerned, this is the first study to evaluate the relation between disease score and muscle atrophy in a model of arthritis.

Filippin L.I., Teixeira V.N., Viacava P.R., Lora P.S., Xavier L.L., Xavier R.M.,Temporal development of muscle atrophy in murine model of arthritis is related to disease severity. J Cachexia Sarcopenia Muscle 2013;3:231-238.

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            Page 239 - 243

Amie J. Dirks-Naylor, Ngan T. K. Tran, Sendra Yang, Raean Mabolo, Samir A. Kouzi

The effects of acute doxorubicin treatment on proteome lysine acetylation status and apical caspases in skeletal muscle of fasted animalsBackground
Doxorubicin treatment is known to cause muscular weakness. However, the cellular mechanisms have not been elucidated. We aimed to determine the effects of acute doxorubicin treatment on proteome lysine acetylation status, an indication of the apoptotic and inflammatory environment, and the expression and activation of various apical caspases involved in the initiation of apoptosis.
Methods
Six-week-old male F344 rats were injected intraperitoneally with 20 mg/kg of doxorubicin or saline. Once the treatment was administered, both groups of animals were fasted with no food or water until sacrifice 24 h posttreatment.
Results
Doxorubicin treatment affected neither the proteome lysine acetylation status nor the expression of sirtuin 1, sirtuin 3, SOD1, or SOD2 in soleus of fasted animals. Doxorubicin treatment also did not affect the expression or activation of procaspase-1, procaspase-8, procaspase-9, or procaspase−12.
Conclusion
We suggest that doxorubicin does not exert a direct effect on these catabolic parameters in skeletal muscle in vivo.

Dirks-Naylor A.J., Tran N.T.K., Yang S., Mabolo R., Kouzi S.A., The effects of acute doxorubicin treatment on proteome lysine acetylation status and apical caspases in skeletal muscle of fasted animals. J Cachexia Sarcopenia Muscle 2013;3:239-243.

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Number 4 / December 2013

            Page 245 - 246

Stephan von Haehling, Stefan D. Anker

Cachexia vs obesity: where is the real unmet clinical need?
A striking discrepancy exists in the number of publications on obesity as compared to cachexia or wasting disorders. In PubMed, the number of entries that contain “cachexia” as a title word is only 1,825, whereas the number of entries for “obesity” in the title is 47,828, giving a ratio of 1:26 in favor of “obesity” publications. The difference in publication activities in these two fields has further broadened over the last years. Looking at guidance from national or international guidelines, PubMed analysis is even more depressing with 147 entries for obesity, but only four for cachexia. None of the latter provides guidance for the everyday care of cachectic patients. This publication activity is in stark contrast to the mortality impact of cachexia vs obesity at the time of diagnosis, which is at least 20 times higher for cachexia over the first 5 years. We assume, the mismatch is even bigger when it comes to public research support for these two medical conditions, which likely is a big part of the reason for this publication imbalance. Another reason may be that there is a perception bias in the research community, the public and hence also among healthcare providers and politicians as to what is important in medicine. We think, cachexia is at least as big an unmet need as is obesity. For shorter-term outcomes, cachexia is certainly a much bigger medical need than obesity. We hope that the current research efforts will change the situation for the better of our patients.

von Haehling S., Anker S.D., Cachexia vs obesity: where is the real unmet clinical need? J Cachexia Sarcopenia Muscle 2013;4:245-246.

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            Page 247 - 257

Manoch Rattanasompattikul, Miklos Z. Molnar, Martin L. Lee, Ramanath Dukkipati, Rachelle Bross, Jennie Jing, Youngmee Kim, Anne C. Voss, Debbie Benner, Usama Feroze, Iain C. MacDougall, John A. Tayek, Keith C. Norris, Joel D. Kopple, Mark Unruh, Csaba P. Kovesdy, Kamyar Kalantar-Zadeh

Anti-Inflammatory and Anti-Oxidative Nutrition in Hypoalbuminemic Dialysis Patients (AIONID) study: results of the pilot-feasibility, double-blind, randomized, placebo-controlled trialBackground
Low serum albumin is common and associated with protein-energy wasting, inflammation, and poor outcomes in maintenance hemodialysis (MHD) patients. We hypothesized that in-center (in dialysis clinic) provision of high-protein oral nutrition supplements (ONS) tailored for MHD patients combined with anti-oxidants and anti-inflammatory ingredients with or without an anti-inflammatory appetite stimulator (pentoxifylline, PTX) is well tolerated and can improve serum albumin concentration.
Methods
Between January 2008 and June 2010, 84 adult hypoalbuminemic (albumin <4.0 g/dL) MHD outpatients were double-blindly randomized to receive 16 weeks of interventions including ONS, PTX, ONS with PTX, or placebos. Nutritional and inflammatory markers were compared between the four groups.
Results
Out of 84 subjects (mean ± SD; age, 59 ± 12 years; vintage, 34 ± 34 months), 32 % were Blacks, 54 % females, and 68 % diabetics. ONS, PTX, ONS plus PTX, and placebo were associated with an average change in serum albumin of +0.21 (P = 0.004), +0.14 (P = 0.008), +0.18 (P = 0.001), and +0.03 g/dL (P = 0.59), respectively. No related serious adverse events were observed. In a predetermined intention-to-treat regression analysis modeling post-trial serum albumin as a function of pre-trial albumin and the three different interventions (ref = placebo), only ONS without PTX was associated with a significant albumin rise (+0.17 ± 0.07 g/dL, P = 0.018).
Conclusions
In this pilot-feasibility, 2 × 2 factorial, placebo-controlled trial, daily intake of a CKD-specific high-protein ONS with anti-inflammatory and anti-oxidative ingredients for up to 16 weeks was well tolerated and associated with slight but significant increase in serum albumin levels. Larger long-term controlled trials to examine hard outcomes are indicated.

Rattanasompattikul M., Molnar M.Z., Lee M.L., Dukkipati R., Bross R., Jing J., Kim Y., Voss A.C., Benner D., Feroze U., MacDougall L.C., Tayek J.A., Norris K.C., Kopple J.D., Unruh M., Kovesdy C.P., Kalantar-Zadeh K. Anti-Inflammatory and Anti-Oxidative Nutrition in Hypoalbuminemic Dialysis Patients (AIONID) study: results of the pilot-feasibility, double-blind, randomized, placebo-controlled trial. J Cachexia Sarcopenia Muscle 2013;4:247-257.

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            Page 259 - 265

Heloisa Veasey-Rodrigues, Henrique A. Parsons, Filip Janku, Aung Naing, Jennifer J. Wheler, Apostolia M. Tsimberidou, Razelle Kurzrock

A pilot study of temsirolimus and body compositionPurpose
Body weight and composition play a role in cancer etiology, prognosis, and treatment response. Therefore, we analyzed the weight, body composition changes, and outcome in patients treated with temsirolimus, an mTor inhibitor that has weight loss as one of its side effects.

Patients and methods
Sixteen patients with advanced solid tumors treated with temsirolimus were studied; body composition was evaluated utilizing computerized tomography images. Sarcopenia was defined as skeletal muscle index lower than 38.5 cm2/m2 for women and 52.4 cm2/m2 for men.

Results
Five of 16 patients (31 %) were men; median age, 60 years. Forty-four percent (7/16) of patients were sarcopenic. Fatigue, anemia, hyperglycemia, and hyperlipidemia were common. Baseline sarcopenia and body composition did not correlate with worse toxicity or treatment outcome. However, there was a trend for greater loss of adipose area (p = 0.07), fat mass (p = 0.09), and adipose index (p = 0.07) for patients with grade 3 or 4 toxicities versus those with grade 1 and 2 side effects.

Conclusion
Patients with higher grade toxicities tended to lose more body fat, suggesting a possible end-organ metabolic effect of temsirolimus. These observations merit exploration in a larger cohort of patients.

Veasey-Rodrigues H., Parsons H.A., Janku F., Naing A., Wheler J.J., Tsimberidou A.M., KurzrockR., A pilot study of temsirolimus and body composition. J Cachexia Sarcopenia Muscle 2013;4:259-265.

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            Page 267 - 275

Anders Nedergaard, Shu Sun, Morten A. Karsdal, Kim Henriksen, Michael Kjær, Yunyun Lou, Yi He, Qinlong Zheng, Charlotte Suetta

Type VI collagen turnover-related peptides—novel serological biomarkers of muscle mass and anabolic response to loading in young menBackground
Immobilization-induced loss of muscle mass is a complex phenomenon with several parallels to sarcopenic and cachectic muscle loss. Muscle is a large organ with a protein turnover that is orders of magnitude larger than most other tissues. Thus, we hypothesize that muscle loss and regain is reflected by peptide biomarkers derived from type VI collagen processing released in the circulation.
Methods
In order to test this hypothesis, we set out to develop an ELISA assay against an type VI collagen N-terminal globular domain epitope (IC6) and measured the levels of IC6 and an MMP-generated degradation fragment of collagen 6, (C6M) in a human immobilization–remobilization study setup with young (n = 11) and old (n = 9) men. They were subjected to 2 weeks of unilateral lower limb immobilization followed by 4 weeks of remobilization including thrice weekly resistance training, using the contralateral leg as internal controls. Subjects were sampled for strength, quadriceps muscle volume and blood at baseline (PRE), post-immobilization (2W), and post-remobilization (4W). Blood were subsequently analyzed for levels of the C6M and IC6 biomarkers. We subsequently tested if there was any correlation between C6M, IC6, or the C6M/IC6 ratio and muscle mass or strength at baseline. We also tested whether there was any relation between these biomarkers and changes in muscle mass or strength with immobilization or remobilization.
Results
The model produced significant loss of muscle mass and strength in the immobilized leg. This loss was bigger in young subjects than in elderly, but whereas the young recovered almost fully, the elderly had limited regrowth of muscle. We found a significant correlation between IC6 and muscle mass at baseline in young subjects (R 2 = 0.6563, p = 0.0045), but none in the elderly. We also found a significant correlation between C6M measured at the 4W time point and the change in muscle mass during remobilization, again only manifesting in the young men(R 2 = 0.6523, p = 0.0085). This discrepancy between the young and the elderly may be caused in part by much smaller changes in muscle mass in the elderly and partly by the relative small sample size.
Conclusion
While we cannot rule out the possibility that these biomarkers in part stem from other tissues, our results strongly indicate that these markers represent novel biomarkers of muscle mass or change in muscle mass in young men.

Nedergaard A., Sun S., Karsdal M.A., Henriksen K., Kjær M., Lou Y., He Y., Zheng Q., Suetta C., Type VI collagen turnover-related peptides—novel serological biomarkers of muscle mass and anabolic response to loading in young men. J Cachexia Sarcopenia Muscle 2013;4:267-275.

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            Page 277 - 285

Dirk Habedank, F. Joachim Meyer, Roland Hetzer, Stefan D. Anker, Ralf Ewert

Relation of respiratory muscle strength, cachexia and survival in severe chronic heart failureBackground
Respiratory muscle (RM) function predicts prognosis in non-cachectic patients with chronic heart failure (CHF). We hypothesized that weakness of RM (maximum inspiratory mouth occlusion pressure, Pimax) is a function of body mass index, and that outcome is more a function of BMI than of Pimax or ventilatory drive (P0.1).

Subjects and methods
We enrolled 249 CHF patients (11.2 % female, median age 54.2 years) at the German Heart Institute Berlin. Patients were in NYHA classes I/II/III/IV by n = 16/90/108/35. All patients underwent tests of pulmonary function, RM (Pimax, P0.1), cardiopulmonary exercise testing (peakVO2, VE/VCO2-slope), and right heart catheterization.

Results
Mean follow-up time was 18 (1–36) months, 47 patients (18.9 %) died or underwent cardiac assist implantation. Pimax correlated weakly with BMI (r = 0.19), peakVO2 (r = 0.15), and FEV1 (r = 0.34, all p < 0.02), and was lower in females compared to males (3.9 ± 1.7 vs. 6.6 ± 2.7 kPa; p < 0.001). P0.1 correlated with pulmonary pressure (rho = 0.2; p < 0.01) and peakVO2 (rho = −0.14; p < 0.02). Neither Pimax [hazard ratio (HR) 0.98; confidence interval (CI) 0.88–1.08] nor P0.1 (HR 0.52; 0.06–4.6) predicted survival. Multivariate regression analysis revealed gender, BMI, and FEV1 as cofactors of Pimax, with only BMI (HR 0.87; CI 0.80–0.95) predicting survival independently. The lowest quintile in BMI had the worst outcome (log-rank χ² = 13.5, p = 0.009).

Summary
In CHF patients including cachexia and NYHA IV, Pimax does not predict survival. Pimax depends on gender, BMI, FEV1, and peakVO2, with only BMI and peakVO2 predicting survival. The impaired Pimax in CHF might be a result of catabolism and weight loss and is not a predictive factor in itself.

Habedank D., Meyer F.J., Hetzer R., Anker S.D., EwertR., Relation of respiratory muscle strength, cachexia and survival in severe chronic heart failure. J Cachexia Sarcopenia Muscle 2013;4:277-285.

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            Page 287 - 293

E. C. A. Hinch, M. J. Sullivan-Gunn, V. C. Vaughan, M. A. McGlynn, Paul A. Lewandowski

Disruption of pro-oxidant and antioxidant systems with elevated expression of the ubiquitin proteosome system in the cachectic heart muscle of nude miceBackground
Current research into the mechanisms of organ atrophy associated with cancer cachexia have centred on the loss of skeletal muscle, as it is one of the most profound physical changes of the disease. However, many patients with cancer cachexia also experience significant atrophy of the heart. The mechanisms causing cardiac tissue wastage in cancer cachexia are largely unknown. However, it is believed to involve a number of molecular interactions between the tumour and host. Increased levels of oxidative stress have been found in cancer cachectic skeletal muscle and has been linked to the activation of the ubiquitin proteosome system (UPS). The aim of the current study was to examine the role of oxidative stress and the UPS in the hearts of mice with cancer cachexia.
Methods
Oxidative damage to DNA (8-OH-2dG), mRNA levels of the ROS-producing enzymes NADPH oxidase (NOX), and xanthine oxidase (XDH), the antioxidant enzyme superoxide dismutase (SOD) and key components of the UPS was measured in the heart of mice with cancer cachexia. Protein expression levels of NOX enzyme subunits and SOD enzyme activity was also measured in the same heart samples.
Results
8-OH-2dG levels were 1.5-fold higher in the heart of mice with cancer cachexia, and this was associated with a 1.7-fold lower level of NOX2 mRNA and twofold higher XDH mRNA in the same hearts. Cancer cachexia was also associated with a 1.5-fold lower level of SOD activity in the heart. Accompanying these pro- and antioxidant differences was a significantly higher level of mRNA for the key UPS elements MURF-1 (4.3=fold) and MAFbx (3.8-fold) in the hearts of mice with cancer cachexia.
Conclusions
The current study demonstrated that cardiac atrophy of cachectic mice is associated with oxidative damage to DNA in the myocardium. The higher levels of XDH mRNA in cachectic hearts suggest that xanthine oxidase may have an important role to play in producing oxidative stress. It appears that the combination of higher XDH expression and lower SOD enzyme activity are key contributors to oxidative stress and cardiac tissue damage in cancer-induced cardiac atrophy. Oxidative stress in the myocardium as with skeletal muscle may also induce increased expression of the E3 ligases MURF-1 and MAFbx as seen in this study.

Hinch E. C. A., Sullivan-Gunn M. J., Vaughan V. C.,McGlynn M. A., LewandowskiP.A. Disruption of pro-oxidant and antioxidant systems with elevated expression of the ubiquitin proteosome system in the cachectic heart muscle of nude mice. J Cachexia Sarcopenia Muscle 2013;4:287-293.

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

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