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      Highlights from the 7th Cachexia Conference: muscle wasting pathophysiological detection and novel treatment strategies.

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          Abstract

          This article highlights preclinical and clinical studies in the field of wasting disorders that were presented at the 7th Cachexia Conference held in Kobe, Japan, in December 2013. This year, the main topics were the development of new methods and new biomarkers in the field of cachexia and wasting disorders with particular focus on inflammatory pathways, growth differentiation factor-15, myostatin, the ubiquitin proteasome-dependent pathway, valosin and the regulation of ubiquitin-specific protease 19 that is involved in the differentiation of myogenin and myosin heavy chain. This article presents highlights from the development of drugs that have shown potential in the treatment of wasting disorders, particularly the ghrelin receptor agonist anamorelin, the myostatin antagonist REGN1033, the selective androgen receptor modulators enobosarm and TEI-E0001, and the anabolic catabolic transforming agent espindolol. In addition, novel data on the prevalence and detection methods of muscle wasting/sarcopenia are presented, including the D3-creatine dilution method and several new biomarkers.

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          Most cited references9

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          Mitochondrial dysfunction and sarcopenia of aging: from signaling pathways to clinical trials.

          Sarcopenia, the age-related loss of muscle mass and function, imposes a dramatic burden on individuals and society. The development of preventive and therapeutic strategies against sarcopenia is therefore perceived as an urgent need by health professionals and has instigated intensive research on the pathophysiology of this syndrome. The pathogenesis of sarcopenia is multifaceted and encompasses lifestyle habits, systemic factors (e.g., chronic inflammation and hormonal alterations), local environment perturbations (e.g., vascular dysfunction), and intramuscular specific processes. In this scenario, derangements in skeletal myocyte mitochondrial function are recognized as major factors contributing to the age-dependent muscle degeneration. In this review, we summarize prominent findings and controversial issues on the contribution of specific mitochondrial processes - including oxidative stress, quality control mechanisms and apoptotic signaling - on the development of sarcopenia. Extramuscular alterations accompanying the aging process with a potential impact on myocyte mitochondrial function are also discussed. We conclude with presenting methodological and safety considerations for the design of clinical trials targeting mitochondrial dysfunction to treat sarcopenia. Special emphasis is placed on the importance of monitoring the effects of an intervention on muscle mitochondrial function and identifying the optimal target population for the trial. This article is part of a Directed Issue entitled: Molecular basis of muscle wasting. Copyright © 2013 Elsevier Ltd. All rights reserved.
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            TGF-b Superfamily Cytokine MIC-1/GDF15 Is a Physiological Appetite and Body Weight Regulator

            The TGF-b superfamily cytokine MIC-1/GDF15 circulates in all humans and when overproduced in cancer leads to anorexia/cachexia, by direct action on brain feeding centres. In these studies we have examined the role of physiologically relevant levels of MIC-1/GDF15 in the regulation of appetite, body weight and basal metabolic rate. MIC-1/GDF15 gene knockout mice (MIC-1−/−) weighed more and had increased adiposity, which was associated with increased spontaneous food intake. Female MIC-1−/− mice exhibited some additional alterations in reduced basal energy expenditure and physical activity, possibly owing to the associated decrease in total lean mass. Further, infusion of human recombinant MIC-1/GDF15 sufficient to raise serum levels in MIC-1−/− mice to within the normal human range reduced body weight and food intake. Taken together, our findings suggest that MIC-1/GDF15 is involved in the physiological regulation of appetite and energy storage.
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              Elevated levels of a C-terminal agrin fragment identifies a new subset of sarcopenia patients.

              Sarcopenia is a recently defined medical condition described as age-associated loss of skeletal muscle mass and function. Recently, a transgenic mouse model was described linking dispersal of the neuromuscular junction caused by elevated agrin degradation to the rapid onset of sarcopenia. These mice show a significant elevation of serum levels of a C-terminal agrin fragment (CAF) compared to wild-type littermates. A series of experiments was designed to ascertain the significance of elevated agrin degradation in the development of human sarcopenia. A quantitative Western blot method was devised to detect CAF in sera of humans. A first trial on consenting blood donors (n=169; age 19-74 years) detected CAF in the limited range of 2.76 ± 0.95 ng/ml. In sarcopenia patients (diagnosed according to clinical and instrumental standards) mean CAF levels were significantly elevated (p=9.8E10-9; n=73; age 65-87 years) compared to aged matched controls. Of all sarcopenia patients, 40% had elevated, non-overlapping CAF levels compared to controls. Evidence is presented for a pathogenic role of the agrin/neurotrypsin system in a substantial subset of sarcopenia patients. These patients are characterized by elevated CAF blood levels compared to aged-matched healthy volunteers suggesting the identification of an agrin-dependent form of sarcopenia. Elevated CAF levels in a large subpopulation of sarcopenic patients suggest the existence of a specific form of sarcopenia for which CAF could become a biomarker and a new target for therapeutic interventions. The feasibility of this approach was demonstrated by the development of a small molecule capable of inhibiting neurotrypsin in vitro and in vivo. Copyright © 2012 Elsevier Inc. All rights reserved.
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                Author and article information

                Journal
                J Cachexia Sarcopenia Muscle
                Journal of cachexia, sarcopenia and muscle
                Springer Nature
                2190-5991
                2190-5991
                Mar 2014
                : 5
                : 1
                Affiliations
                [1 ] Applied Cachexia Research, Department of Cardiology, Charité Medical School, Campus Virchow-Klinikum, Augustenburger Platz 1, 13353, Berlin, Germany.
                Article
                10.1007/s13539-014-0136-z
                3953317
                24595460
                07869bc2-9933-4b6d-b0d7-818e06feae18
                History

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