Satellite stem cell biology

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DESCRIPTION (provided by applicant): 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.