A loss of skeletal muscle functional capacity occurs in disease, disuse and aging mostly attributable to a loss of muscle mass. Such losses of muscle mass contribute to weakness, impaired mobility and/or respiratory function, low quality of life and high health care costs. The overall goal of this proposal is to delineate cellular and molecular mechanisms that regulate growth of atrophied muscles. The relative importance of muscle precursor cell (mpc) pathways vs. myofiber pathways can vary depending on the type of muscle growth and may differ for the growth of an atrophied myofiber. Determining how much of the recovery from atrophy is dependent on mpc is important for designing therapeutic strategies to treat muscle atrophy. This proposal has 3 integrated parts: (1) To delineate the contribution of mpc and other muscle progenitor cells to growth of atrophied muscle (Aims 1 and 2). We will define the timing of mpc proliferation and fusion with myofibers during growth. Subsequently, we will analyze growth in muscles lacking mpc due to local irradiation. Finally, we will determine if the abundance and/or in vitro properties of newly identified muscle progenitor populations change in response to muscle atrophy or growth. (2) To enhance mpc proliferation and fusion using the drug curcumin as a means of stimulating recovery from atrophy (Aim 3). We have previously shown that curcumin effectively enhances the growth of regenerating muscles and now extend these studies to growth of atrophied muscle; (3) To study molecular signals that are activated during the growth of atrophied muscles (Aims 4 and 5). We will delineate the contribution of a known signaling pathway (calcineurin) as well as identify new molecules using microarray analysis, which may play a role in regulating muscle growth. The experiments in this proposal will reveal new information about growth of atrophied muscle and possibly new avenues of rehabilitative therapy for manipulating this growth process in disease, disuse and aging.

National Institute of Health (NIH)
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Research Project (R01)
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Geriatrics and Rehabilitation Medicine (GRM)
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Nuckolls, Glen H
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Emory University
Schools of Medicine
United States
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