mTOR Signaling in Skeletal Myogenesis

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DESCRIPTION (provided by applicant): Skeletal muscle differentiation is a well-orchestrated process regulated by autocrine, paracrine, and endocrine factors via multiple signal transduction pathways. The bacterial macrolide rapamycin inhibits a wide spectrum of cellular functions, from proliferation, growth, to differentiation, and it has served as a powerful tool to probe relevant signaling pathways. While the rapamycin-sensitive pathway is under intensive investigation in the context of cell growth and proliferation, its importance in skeletal muscle development is only beginning to be recognized. The mammalian target of rapamycin - mTOR- is a multi-functional protein that serves as a central component of multiple signaling pathways that are inhibited by rapamycin. Preliminary studies from this investigator's laboratory have revealed an essential function of mTOR in skeletal muscle differentiation and the existence of novel mechanisms of mTOR signaling. The proposed studies are designed to test the hypothesis that an mTOR pathway distinct from that in cell growth and proliferation regulates skeletal muscle satellite cell differentiation by controlling the autocrine production of IGF-I and IGF-II. With a combination of biochemical, molecular, cellular and genetic approaches, and in the systems of a tissue culture model (C2C12) and mouse primary satellite cells, the specific aims of this proposal are to investigate (1) regulation of IGF autocrine production by mTOR; (2) involvement of a phospholipase D-phosphatidic acid-mTOR pathway in myogenesis; and (3) mTOR's structure-function relationship and novel signaling partners in differentiation. Knowledge gained in these studies will not only provide invaluable insights into the signaling mechanisms of the pleiotropic mTOR pathway, but also make significant contributions to the molecular understanding of skeletal muscle development, which is tightly coupled to health-related issues such as muscular dystrophy, exercise-induced hypertrophy, and aging-related atrophy.