Repression of Skeletal Myogenesis

University Of Florida, Gainesville FL

Investigators

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Abstract

DESCRIPTION (provided by applicant): Improved nutrition and healthcare are just two of a plethora of factors contributing to the increased longevity of the American people. Coincident with the increased life expectancy is a steady decline in ambulatory function, a product of age-associated atrophy of muscle tissue. The loss in mobility with age is a consequence of both fewer muscle cells and a reduction in cell size. With a trend toward increasing the average lifespan of an individual, a concomitant rise in muscle disuse and atrophy will follow leading to quality of life concerns and rising healthcare costs for the immobile elderly. Thus, it is imperative that our understanding of the basic processes of muscle formation be significantly advanced such that novel therapeutic approaches can be developed to alleviate muscle atrophy. We have identified an essential signaling pathway that negatively impacts myofiber development. Chronic activation of Raf kinase initiated phosphorylation events suppresses myofiber formation and muscle gene expression. The molecular means by which Raf disrupts skeletal muscle formation may involve synthesis and secretion of a TGF-beta-like protein as well as stimulation of alternate signaling pathways. By further characterization of the Raf kinase intracellular signaling modules present in skeletal myoblasts, we can pinpoint critical downstream effectors that participate in the block to optimal muscle formation and thereby, provide targets for intervention therapy. Therefore, the Specific Aims of this grant are: 1. To establish that activated Raf signaling induces expression of members of the TGF-beta superfamily of genes that leads to the creation of an autocrine myogenic inhibitory loop. 2. To identify novel Raf-interacting proteins that participate in the atypical MEK-independent block to muscle formation. 3. To delineate the molecular basis for Raf-induced positive and negative regulation of myogenic gene transcription.