Loss of skeletal muscle mass is a devastating complication of a wide range of diseases and conditions. However, there is still no approved therapy to prevent muscle wasting partly because the mechanisms that regulate skeletal muscle mass remain enigmatic. Accumulating evidence suggests that an array of signaling pathways regulates skeletal muscle mass mainly through modulating the rate of protein synthesis and degradation. However, upstream signaling mechanisms that are involved in the regulation of muscle mass remain poorly understood. During the current funding of this project, we showed TRAF6 mediates muscle atrophy and inhibits muscle regeneration in a variety of catabolic conditions. We also demonstrated that TRAF6 and TAK1 are important regulators of satellite cell homeostasis in adult skeletal muscle. In contrast to TRAF6, of which activation, causes muscle wasting, we have discovered that TAK1 is essential for skeletal muscle growth and maintenance of muscle mass in adults. Inducible myofiber-specific inactivation of TAK1 in mice (henceforth TAK1mko) leads to severe muscle wasting and development of kyphosis. The positive role of TAK1 in muscle growth is also supported by our findings that the activation of TAK1 is dramatically increased in skeletal muscle undergoing hypertrophy. Our experiments also suggest that TAK1 is required for the activation of specific intracellular pathways which promote skeletal muscle growth. Moreover, our studies indicate that TAK1 may be required for the activation of autophagy/mitophagy, regulation of mitochondrial structure and function, and maintenance of redox balance in skeletal muscle of adults. Based on our preliminary data, we hypothesize that (I) TAK1 promotes skeletal muscle growth and inhibits atrophy through augmenting protein synthesis and preventing oxidative stress; (II) TAK1 induces the activation of specific intracellular signaling pathways to augment skeletal muscle mass; and (III) TAK1 is required for the activation of autophagy/mitophagy and regulation of mitochondrial dynamics (i.e. biogenesis, fusion, and fission) and respiratory function in adult skeletal muscle. To test these hypotheses, in the next phase of the project, we propose to address the following three specific aims: (1) Establish the role and investigate the molecular mechanisms by which TAK1 promotes skeletal muscle growth and prevents atrophy; (2) Investigate the signaling mechanisms by which TAK1 regulates skeletal muscle mass; and (3) Investigate the role of TAK1 in regulation of autophagy and mitochondrial content and function in adult skeletal muscle.

Public Health Relevance

While the maintenance of skeletal muscle mass and function is prerequisite for whole body health throughout life, loss of skeletal muscle mass is a debilitating consequence of many chronic disease states and conditions. Unfortunately, there is still no approved therapy for treatment of this syndrome. Our proposed studies will identify molecular and signaling mechanisms by which TAK1 improves skeletal muscle mass in adults. Successful completion of this project will enhance the basic understating of etiology of muscle growth and atrophy and may lead to the identification of TAK1 as a novel drug target to improve muscle mass and function in human population.

National Institute of Health (NIH)
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Research Project (R01)
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Special Emphasis Panel (ZRG1)
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Boyce, Amanda T
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University of Louisville
Anatomy/Cell Biology
Schools of Medicine
United States
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Bohnert, Kyle R; McMillan, Joseph D; Kumar, Ashok (2018) Emerging roles of ER stress and unfolded protein response pathways in skeletal muscle health and disease. J Cell Physiol 233:67-78
Hindi, Sajedah M; Sato, Shuichi; Xiong, Guangyan et al. (2018) TAK1 regulates skeletal muscle mass and mitochondrial function. JCI Insight 3:
Gallot, Yann S; Straughn, Alex R; Bohnert, Kyle R et al. (2018) MyD88 is required for satellite cell-mediated myofiber regeneration in dystrophin-deficient mdx mice. Hum Mol Genet 27:3449-3463
Xiong, Guangyan; Hindi, Sajedah M; Mann, Aman K et al. (2017) The PERK arm of the unfolded protein response regulates satellite cell-mediated skeletal muscle regeneration. Elife 6:
Hindi, Sajedah M; Shin, Jonghyun; Gallot, Yann S et al. (2017) MyD88 promotes myoblast fusion in a cell-autonomous manner. Nat Commun 8:1624
Hindi, Lubna; McMillan, Joseph D; Afroze, Dil et al. (2017) Isolation, Culturing, and Differentiation of Primary Myoblasts from Skeletal Muscle of Adult Mice. Bio Protoc 7:
de Carvalho, Samara Cama├žari; Hindi, Sajedah M; Kumar, Ashok et al. (2017) Effects of omega-3 on matrix metalloproteinase-9, myoblast transplantation and satellite cell activation in dystrophin-deficient muscle fibers. Cell Tissue Res 369:591-602
Gallot, Yann S; McMillan, Joseph D; Xiong, Guangyan et al. (2017) Distinct roles of TRAF6 and TAK1 in the regulation of adipocyte survival, thermogenesis program, and high-fat diet-induced obesity. Oncotarget 8:112565-112583
Simionescu-Bankston, Adriana; Kumar, Ashok (2016) Noncoding RNAs in the regulation of skeletal muscle biology in health and disease. J Mol Med (Berl) 94:853-66
Hindi, Sajedah M; Kumar, Ashok (2016) TRAF6 regulates satellite stem cell self-renewal and function during regenerative myogenesis. J Clin Invest 126:151-68

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