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

描述（由申请人提供）：运动已被证明是治疗许多影响肌肉功能的疾病的有力干预措施。运动的积极作用在很大程度上被认为是线粒体数量和功能变化的结果。运动介导线粒体变化的方式尚不清楚。过氧化物酶体增殖体激活受体γ共激活因子-1 （PGC-1）家族的成员已被确定为对正常肌肉和线粒体功能都很重要。人们普遍认为，PGC-1是运动后这些变化的大部分原因，如果不是全部的话。然而，我们观察到骨骼肌中PGC-1¿的缺失并不影响线粒体参数的适应性变化。这些数据表明，运动引起的线粒体变化并不需要PGC-1¿。此外，线粒体动力学（融合/裂变）在改善运动后肌肉功能中的作用尚不清楚，其对去除不良和受损线粒体的贡献也未得到研究。这些观察结果表明，我们对运动引起的骨骼肌变化的理解是不完整的。因此，本提案的总体目标是了解运动和PGC-1s如何影响线粒体数量和动力学以提高肌肉表现。利用遗传模型、细胞成像和线粒体分析，我们将尝试解决这些非常重要的问题。这一建议的结果对我们理解运动在治疗线粒体疾病中的益处具有广泛的意义。具体目的是：1)确定PGC-1¿和¿在调节运动诱导的线粒体生物发生中的作用；2)确定运动与PGC-1¿和¿在调节线粒体融合和裂变中的作用；3)核聚变/裂变试验

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.