Regulation of Mitochondria by Exercise and PGC-1 Coactivators in Skeletal Muscle

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DESCRIPTION (provided by applicant): Exercise has been shown to be a powerful intervention for the treatment of many diseases that affect muscle function. The positive effects of exercise are largely considered to be the result of changes in both the number and functionality of mitochondria. The ways in which exercise mediates the changes in mitochondria are poorly understood. Members of the peroxisome proliferator-activated receptor gamma coactivator-1 (PGC-1) family of coactivators have been identified as being important to both normal muscle and mitochondria function. It is widely suggested that PGC-1¿ is responsible for most, if not all, of these changes in response to exercise. However, we observe that deletion of PGC-1¿ in skeletal muscle does not affect the adaptive changes in mitochondrial parameters. These data show that PGC-1¿ is not required for exercise-induced changes in mitochondria. In addition, the role that mitochondrial dynamics (fusion/fission) in improving muscle function in response to exercise is unknown and its contribution to removing bad and damaged mitochondria is unstudied. These observations reveal that our understanding of exercise-induced changes in skeletal muscle is incomplete. Therefore, the overall objective of this proposal is to understand how exercise and the PGC-1s affect mitochondria number and dynamics to improve muscle performance. Using genetic models, cellular imaging and mitochondrial assays we will attempt to address these very important questions. Results from this proposal have broad implications for our understanding of the benefits of exercise in the treatment of mitochondrial disorders. The specific aims are to: 1) determine the contribution of PGC-1¿ and ¿ in regulating exercise-induced mitochondrial biogenesis; 2) determine the role of exercise and PGC-1¿ and ¿ in regulating mitochondrial fusion and fission; 3) test if fusion/fission is involved in the dramatic improvement conferred by exercise seen with advance aging. The candidate is completing his postdoctoral training in the Cardiovascular Institute (CVI) at Beth Israel Deaconess Medical Center (BIDMC), a teaching hospital of Harvard Medical School. His primary mentor is Dr. Zoltan Arany, Assistant Professor of Medicine, with extensive experience in PGC-1 coactivators, molecular biology and metabolism. His co-mentor is Dr. Laurie Goodyear, Associate Professor of Medicine, a world-renowned expert in exercise physiology and skeletal muscle. The candidate's long-term career goal is to establish an independent research program in exercise physiology and mitochondrial dynamics. To accomplish this goal, he has created a series of short-term goals designed to enhance his knowledge of mitochondrial function, skeletal muscle, exercise physiology and advanced imaging technology, which will be facilitated by his mentorship oversight team and a comprehensive career development plan. Results from this proposal will serve as the foundation and preliminary data for an R series proposal such as an R01 within 3-5 years. PUBLIC HEALTH RELEVANCE: Exercise has been proven to be one of the best interventions in many disorders of the skeletal muscle system, such as diabetes and age-associated muscle wasting. However, the ways in which the beneficial effects of exercise are propagated within muscle are poorly understood. The purpose of this study is to determine how mitochondria are able to respond to exercise, thereby improving skeletal muscle performance.