Chronic alcohol-induced skeletal muscle myopathy: etiology & physiology

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Career Goals: My research career goals are to study the effects of alcohol abuse on skeletal muscle structure and function, and to develop clinically effective treatments for alcoholic myopathy. I plan to obtain these goals as a PI in an academic laboratory. Through this proposal, I will gain experience in several new techniques, including, muscle mechanic measures, HPLC, siRNA, luciferase assays, and flow cytometry. Research Project: In 2001, the National Institute on Alcohol Abuse and Alcoholism estimated that nearly 18 million adult Americans abused alcohol or were alcoholics. Chronic alcohol abuse, defined as alcohol ingestion in excess of 100 g/d for more than 10 years, can produce severe, pathological derangements to various tissues, including lungs, liver, heart, and skeletal muscle. Skeletal muscle myopathy due to excessive alcohol ingestion, termed alcoholic myopathy, occurs in 45-70% of alcoholics and is at least five times more prevalent than cirrhosis. These derangements in skeletal muscle structure and function are likely multi-factorial in origin, but may be regulated, in part, by alcohol-induced oxidative stress and reduced antioxidant levels. Yet, the molecular mechanisms stimulated by alcohol-induced oxidative stress and their influence on skeletal muscle structure and function remain poorly defined. Therefore, the long-term objectives of this proposal are to identify a root cause of alcoholic myopathy and to provide feasible and clinically effective treatments to combat the disease. We have recently published data that show chronic alcohol abuse increases oxidative stress with specific alterations to components of the glutathione cycle in rat skeletal muscle (39). Further, expressions of atrogin-1 and Transforming Growth Factor-p (TGF(3), two factors associated with skeletal muscle atrophy, are strongly induced in these skeletal muscles. Importantly, glutathione supplementation attenuated oxidant stress and expression of these catabolic factors. Therefore, in three integrated specific aims, experiments will be designed using distinct glutathione precursors in attempts to attenuate the alcohol-induced, redox-sensitive atrogin-1 /TGF3 pathway and to ultimately preserve skeletal muscle structure and function. Relevance: These studies have relevance for defining major molecular, biochemical and physiological pathways that regulate alcoholic myopathy. Further, given the clinical effectiveness of glutathione replacement therapy in other alcohol-induced tissue injuries, the results from this K01 proposal will likely provide very successful therapeutic strategies that prevent symptoms of this disease.