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TELOMERE DYNAMICS AND REGULATION: EFFECTS OF CHRONIC EXERCISE, ACUTE EXERCISE, AND OXIDATIVE STRESS
Ludlow, Andrew Todd
Roth, Stephen M
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This dissertation research is comprised of three studies each examining the effects of chronic exercise, acute exercise, or oxidative stress on telomere biology. Exercise training and physical activity have previously been associated with telomere maintenance, but the underlying mechanisms of this association are unclear. The majority of studies to date have been performed in immune cells; however, the findings from these cells may not reflect telomere biology in other tissues. Since exercise is a multi-organ stimulus we sought to describe the effect of exercise on telomere biology in multiple tissues, with a particular focus on skeletal muscle. Study #1 showed that the effect of chronic voluntary exercise on telomere length in CAST/Ei mice is tissue specific. Exercise was `telo-protective' (i.e., maintained telomere length) in cardiac and liver tissues, while telomere shortening was observed in skeletal muscle of exercised animals compared to sedentary and young mice. Study #2 was performed to elucidate the responses to acute exercise that could underlie the paradoxical response of telomere length in skeletal muscle to exercise training. This study revealed that the MAPK pathway appears to be related to the expression of telomere binding proteins in response to acute exercise. In skeletal muscle, p38 MAPK mediated a decrease in gene expression of telomere binding proteins, providing insight into a possible mechanism for eventual telomere shortening in response to chronic exercise. The results of study #2 indicate that the early cellular responses to exercise may accumulate (i.e., repeat bout effect) and underlie the shortened telomere length in skeletal muscle. Study #3 sought to determine if reactive oxygen species were a plausible mechanism of telomere shortening in adult skeletal muscle fibers, as no mechanism to date has been elucidated for telomere shortening in this tissue. Study #3 showed that oxidative stress is a potent telomere- shortening stimulus in skeletal muscle fibers of mice and that telomere binding protein expression was also significantly affected by oxidative stress. In total these results indicate that although chronic exercise attenuates telomere shortening in most tissues, skeletal muscle demonstrates a unique contradictory response likely due to its reaction to oxidative stress.