Satellite cells are muscle-specific stem cells that function to repair damaged myofibers and provide new myonuclei for muscle enlargement. Rosenblatt has shown that knocking out the proliferative capacity of satellite cells prevents hypertrophy of skeletal muscle. Blau and Wright have found that satellite cells prematurely senesce in young patients with Duchenne's muscular dystrophy who have many cycles of regeneration. Schultz has observed a progressive loss of the proliferative capacity of satellite cells as rats age, and similar data has just been reported in humans. Hayflick showed that normal, diploid cells have a finite proliferative lifespan and reach cellular senescence. However, Bischoff indicated that a critical evaluation of the self-maintenance criteria required to categorize the satellite cell as stem cell is yet to be undertaken. These provocative reports highlight some of the conceptual framework to pose the following specific aims. Using the well-established and validated approach of clonogenecity assays to determine a cell's proliferation potential, this proposal examines 1.) whether a physiological model of repeated cycles of atrophy-regrowth in old skeletal muscle speeds satellite cells to senescence so that their proliferative capacity is depleted prior to the lifespan of rats; 2.) determine whether the application of IGF-1 to skeletal muscle or 3.) increased contractile activity, or both aims 1 and 2 results in either a.) using up or b.) replenishing the finite population doublings in old satellite cells. These results would shed much needed insight into whether replicative senescence can be modulated by environmental factors. The information thus gleaned from these studies will provide the basis for follow-up experiments that will measure cell cycle markers to begin to explain the observations in molecular detail. As the number of individuals with frailty is rapidly increasing, it becomes a more urgent clinical, social, and economic issue to find out if and how satellite cell lifespan can be maintained/enhanced. This proposal will therefore provide novel insights into how the self-maintenance properties of satellite cells is modulated by compensatory factors (IGF-1 and exercise), thereby forming the basis for more effective interventions against senile-atrophy and frailty.
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