Skeletal muscle is the locus of biochemical abnormalities in variety of pathological stress, the most common of which is non-insulin dependent diabetes mellitus or NIDDM. Recent advances in biochemistry, cellular and molecular biology have identified some of the events that regulate muscle development and differentiation. In addition, they have provided new insight into the phenotype of terminally differentiated muscle. Specifically, the insulin-like growth factors (IGFs) appear to play a major role in mediating the differentiation of muscle, a process that involves the expression of genes encoding myogenic factors (e.g., MyoD1 and myogenin), which in turn, regulate the expression of structural genes. In adult muscle, insulin plays a major role in nutritional homeostasis in large part through its action in muscle mediated via the expression of issue-specific genes. This program project brings together investigators who are addressing the role of insulin and the IGFs in muscle development, differentiation and metabolism. We will examine the postulate that the IGFs and other growth factors (TGF Beta, FGF) regulate aspects of muscle development in the embryo and in cell culture models of muscle differentiation. We will study the mechanism by which insulin (and IGFs) regulates the expression of certain genes including glycerophosphate dehydrogenase and myosin light chain, a marker of terminal differentiation. We will identify, characterize and clone cDNAs for novel proteins involved in the ontogeny of the insulin response in mature muscle, and we will elucidate the role of diacylglycerol and protein kinase C in insulin- mediated signal transduction pathway(s) in adult skeletal muscle. We will ultimately exploit the potential of myoblast implantation as an adjunct for diabetes. We anticipate that the proposed research will lead to increased basic knowledge of both muscle biology and the roles of insulin and IGF-1 in regulating muscle-specific gene expression. Such knowledge will doubtless be essential to the understanding and treatment of pathological conditions such as diabetes.
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