A massive increase in the number of humans with sarcopenia, and the resulting burden of their disability, suffering, and the expense of assisted care living is occurring. Skeletal muscle growth failures have been reported in aged humans and hypertrophy models of aged animals. Following atrophy by hindlimb immobilization, skeletal muscle in aged rats does not regrow for 77 days, whereas in young rats regrowth is strikingly complete by 30 days. These facts suggest an urgency to understand cellular mechanisms producing muscle atrophy and weakness in the elderly. The long-term objective of this proposal is to gain a better understanding of factors impairing proliferation and differentiation of muscle progenitor cells during aging and physical inactivity, which accelerates muscle wasting during aging. As IGF-I rescues sarcopenia and the failure of muscle to regrow from immobilization in the old rats, Specific Aim 1 will extend these observations to cellular mechanisms. The general hypothesis of Specific Aim 1 is that IGF-I regulates the expression of p27Kip1, Gadd45, and MnSOD genes through nuclear FoxO1 levels in primary rat muscle progenitor cells of aging Fischer 344 x Brown Norway rats. A paradigm of medicine is to identify molecules responsible for pathologies to improve prevention and cures, which is one goal of Specific Aim 1.
Specific Aim 2 will determine the roles that p53 and Sir2 play in impairing the proliferative and myogenic potential of muscle progenitor cells taken from skeletal muscles of old animals or from immobilized limbs of young and old animals. Overexpression and silencing of p53 and Sir2 will be employed to produce gain and loss of function, respectively.
Specific Aim 3 will employ transcript profiling to identify previously unidentified mRNA differences in satellite cells, the side population of satellite cells, and differentiating myotubes at young, adult, I and old ages in order to provide novel candidate factors which can be tested for contributing to the differences l in cell behavior with aging. From the identified mRNAs, genes will be selected for cloning and functional l analysis to determine if their overexpression or silencing alters muscle cell phenotype in a manner consistent I with the aging phenotype. The outcomes of the research will provide a more scientific basis to devise therapies to prevent and treat sarcopenia and physical frailty.

National Institute of Health (NIH)
National Institute on Aging (NIA)
Research Project (R01)
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Skeletal Muscle and Exercise Physiology Study Section (SMEP)
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Williams, John
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University of Missouri-Columbia
Veterinary Sciences
Schools of Veterinary Medicine
United States
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Zwetsloot, K A; Childs, T E; Gilpin, L T et al. (2013) Non-passaged muscle precursor cells from 32-month old rat skeletal muscle have delayed proliferation and differentiation. Cell Prolif 46:45-57
Zwetsloot, Kevin A; Nedergaard, Anders; Gilpin, Leigh T et al. (2012) Differences in transcriptional patterns of extracellular matrix, inflammatory, and myogenic regulatory genes in myofibroblasts, fibroblasts, and muscle precursor cells isolated from old male rat skeletal muscle using a novel cell isolation procedure. Biogerontology 13:383-98
Dumke, Breanna R; Lees, Simon J (2011) Age-related impairment of T cell-induced skeletal muscle precursor cell function. Am J Physiol Cell Physiol 300:C1226-33
Booth, F W; Zwetsloot, K A (2010) Basic concepts about genes, inactivity and aging. Scand J Med Sci Sports 20:1-4
Rathbone, Christopher R; Booth, Frank W; Lees, Simon J (2009) Sirt1 increases skeletal muscle precursor cell proliferation. Eur J Cell Biol 88:35-44
Lees, Simon J; Zwetsloot, Kevin A; Booth, Frank W (2009) Muscle precursor cells isolated from aged rats exhibit an increased tumor necrosis factor- alpha response. Aging Cell 8:26-35
Shanely, R Andrew; Zwetsloot, Kevin A; Childs, Thomas E et al. (2009) IGF-I activates the mouse type IIb myosin heavy chain gene. Am J Physiol Cell Physiol 297:C1019-27
Zwetsloot, Kevin A; Laye, Matthew J; Booth, Frank W (2009) Novel epigenetic regulation of skeletal muscle myosin heavy chain genes. Focus on ""Differential epigenetic modifications of histones at the myosin heavy chain genes in fast and slow skeletal muscle fibers and in response to muscle unloading"". Am J Physiol Cell Physiol 297:C1-3
Booth, F W; Laye, M J (2009) Lack of adequate appreciation of physical exercise's complexities can pre-empt appropriate design and interpretation in scientific discovery. J Physiol 587:5527-39
Jump, Seth S; Childs, Tom E; Zwetsloot, Kevin A et al. (2009) Fibroblast growth factor 2-stimulated proliferation is lower in muscle precursor cells from old rats. Exp Physiol 94:739-48

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