Adequate muscle mass and function are critical for human health. Skeletal muscle comprises ~50-60% of total body mass and is one of the major tissues involved in regulating metabolism, locomotion and strength. Loss of muscle mass results in weakness and impaired motility, and if severe enough, in increased morbidity and mortality. Therefore, defining the molecular and cellular pathways that regulate growth of skeletal muscle is critical for human health. Our lab has shown non-redundant roles for different members of the NFAT family of transcription factors in skeletal muscle growth, specifically the NFATc2 and NFATc3 isoforms. Recently a new isoform of NFAT, NFAT5, has been discovered, which displays many differences from the conventional NFAT family members. Our recent data indicates NFAT5 is expressed in muscle cells and regulates multiple phases of myogenesis. In addition, our preliminary data show that creatine, an activator of NFAT5 transcriptional activity, enhances muscle growth. Furthermore, downstream targets of NFAT5 signaling regulate myogenesis. The overall goal of this proposal is to determine how the NFAT5 signaling pathway regulates muscle growth using an integrated approach in vivo and in vitro. A set of 4 aims are proposed to analyze NFAT5 function during muscle growth during muscle regeneration in vivo (Aim 1), determine the role of NFAT5 in regulating myoblast proliferation, migration, differentiation and fusion in vitro (Aim 2), analyze the NFAT5-dependent and -independent roles of creatine on muscle growth (Aim 3) and study the role of a newly identified NFAT5 target gene in myogenesis (Aim 4). A combination of cellular and molecular approaches will be utilized. Our proposed studies will define a novel pathway in muscle for regulating muscle growth. Understanding the role of the NFAT5 pathway in regulating muscle size may lead to new strategies for manipulating muscle cells in disease, repair and aging and define novel therapeutic targets for enhancing muscle growth.

National Institute of Health (NIH)
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Research Project (R01)
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Skeletal Muscle and Exercise Physiology Study Section (SMEP)
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Boyce, Amanda T
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Emory University
Schools of Medicine
United States
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Simionescu-Bankston, Adriana; Pichavant, Christophe; Canner, James P et al. (2015) Creatine kinase B is necessary to limit myoblast fusion during myogenesis. Am J Physiol Cell Physiol 308:C919-31
Simionescu-Bankston, Adriana; Leoni, Giovanna; Wang, Yanru et al. (2013) The N-BAR domain protein, Bin3, regulates Rac1- and Cdc42-dependent processes in myogenesis. Dev Biol 382:160-71
Abmayr, Susan M; Pavlath, Grace K (2012) Myoblast fusion: lessons from flies and mice. Development 139:641-56
Simionescu, Adriana; Pavlath, Grace K (2011) Molecular mechanisms of myoblast fusion across species. Adv Exp Med Biol 713:113-35
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Hall, Monica N; Corbett, Anita H; Pavlath, Grace K (2011) Regulation of nucleocytoplasmic transport in skeletal muscle. Curr Top Dev Biol 96:273-302
Pavlath, Grace K (2010) A new function for odorant receptors: MOR23 is necessary for normal tissue repair in skeletal muscle. Cell Adh Migr 4:502-6
Griffin, Christine A; Apponi, Luciano H; Long, Kimberly K et al. (2010) Chemokine expression and control of muscle cell migration during myogenesis. J Cell Sci 123:3052-60
Pavlath, Grace K (2010) Spatial and functional restriction of regulatory molecules during mammalian myoblast fusion. Exp Cell Res 316:3067-72
Griffin, Christine A; Kafadar, Kimberly A; Pavlath, Grace K (2009) MOR23 promotes muscle regeneration and regulates cell adhesion and migration. Dev Cell 17:649-61

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