EXCEED THE SPACE PROVIDED. Muscle wasting remains a cause of morbidity and mortality in patients with a history of chronic alcohol abuse. This myopathy appears to be predominantly due to a decreased rate of protein synthesis. Our previous work revealed that alcohol impaired translational control of protein synthesis by modulating key steps in peptide-chain initiation. Furthermore, our studies indicate that alterations in different components of the insulin-like growth factor (IGF) system are central to the observed defects in protein synthesis. Specifically, chronic alcohol feeding decreases the content of IGF-I in the blood and within muscle, thereby decreasing the availability of this key anabolic factor. Furthermore, alcohol feeding elevates one of the IGF binding proteins, IGFBP-1, which we have demonstrated decreases IGF-I bioactivity. Finally, our preliminary data suggest a putative role for myostatin, a negative regulator of muscle mass, and TNFa, a proinflammatory cytokine, in the observed myopathy. The working hypothesis to be tested is that interactions between components of the IGF system, myostatin and TNFa modulate specific key regulatory steps in peptide-chain initiation thereby decreasing protein synthesis in muscle. To address the questions implicit in this hypothesis, the proposed research has the following specific aims: (1) to determine the mechanism bywhich alcohol impairs the normal stimulatory effect of IGF-I on muscle protein synthesis; (2) to determine which components of the IGF-I signal transduction pathway in muscle are altered by chronic alcohol consumption; (3) to determine the role that TNFa plays in mediating the alcohol-induced myopathy; (4) to determine the mechanism by which the alcohol- induced increase in IGF binding protein (IGFBP)-1 impairs muscle protein synthesis; and (5) to determine the mechanism by which alcohol and TNFa modulate IGF-I and myostatin action in cultured myocytes. These studies integrate in vivo and in situ measurements of the IGF system and protein synthesis with in vitro studies aimed at elucidating cellular mechanisms. The proposed research will provide novel information on the cellular mechanisms by which chronic alcohol consumption regulates key anabolic (e.g. IGF-I) and catabolic (IGFBP-1, myostatin and TNFa) factors, and how these factors interrelate to regulate translational control of protein synthesis in skeletal muscle, leading to a more thorough understanding of alcoholmyopathy. PERFORMANCE SITE ========================================Section End===========================================
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