TAK1/TRAF6 Signaling in Skeletal Muscle

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DESCRIPTION (provided by applicant): Skeletal muscle atrophy/wasting is a devastating complication of a wide range of diseases and conditions such as aging, disuse, chronic obstructive pulmonary disease, space travel, chronic heart failure, sepsis, and cancer. Myogenesis is the process that is required not only for the embryonic development of skeletal muscle but it is also an important element of certain types of postnatal growth and repair of injured myofibers. Impairment in myogenesis is the critical determinant of skeletal muscle-wasting in several chronic diseases and also development of rhabdomyosarcoma in children. Although significant progress has been made to understanding the processes of skeletal muscle formation and wasting, the upstream signaling events regulating skeletal muscle mass in various physiological and pathophysiological conditions remain poorly understood. We have accumulated strong evidence that supports a crucial role of TAK1/TRAF6 signaling complex in the acquisition and maintenance of skeletal muscle mass. Our preliminary studies have shown that both TRAF6 and TAK1 stimulate myogenic differentiation through novel Lysine-63-linked poly-ubiquitination mechanisms. TAK1 and TRAF6 are also required for MyoD-induced transformation of non-muscle cells into skeletal muscles. In adult skeletal muscle, the activation of TAK1/TRAF6 leads to inflammation, impairment in myofiber regeneration, and atrophy. To clearly establish the role and delineate the mechanisms of action of TAK1/TRAF6 complex in skeletal muscle, we will use genetic approaches including conditional knockout mice. Based on our preliminary data, we hypothesize that signaling through TAK1 and TRAF6 is required for the development of skeletal muscle but not for maintaining differentiated phenotype. Under stress conditions, the activation of TAK1 and TRAF6 stimulates catabolic pathways leading to skeletal muscle atrophy. To test this hypothesis, we propose to address the following three specific aims: 1) Investigate the signaling mechanisms by which TAK1 and TRAF6 regulate myogenic differentiation in cultured myoblasts; 2) Investigate the role and cellular mechanisms by which TAK1 and TRAF6 regulate skeletal muscle development in vivo; and 3) Delineate the mechanisms by which TAK1 and TRAF6 regulates regeneration and atrophy in adult skeletal muscles. Successful completion of this project will provide critical insights into the signaling mechanisms and establish TAK1 and TRAF6 as novel molecular targets to prevent skeletal muscle loss in various muscular disorders. PUBLIC HEALTH RELEVANCE: Skeletal muscle formation and wasting are well-orchestrated processes regulated by autocrine, paracrine, and endocrine factors via multiple signal transduction pathways. Our proposed studies are aimed to dissect the signaling mechanisms underlying the regulation of muscle differentiation with a focus on TAK1/TRAF6 complex. In addition to muscle formation, our study will also delineate the signaling mechanisms responsible for accelerated protein degradation that causes rapid atrophy of mature skeletal muscles. Results of these studies will contribute to the understanding of skeletal muscle biology, which will have a significant impact on health-related issues such as sarcopenia, disease- induced muscle atrophy, muscle regeneration, and rhabdomyosarcoma.