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手段。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改变的结果。人们对运动调节线粒体变化的方式知之甚少。过氧化物酶体增殖物激活受体-1共激活剂-1(PGC-1)家族的成员被认为对正常肌肉和线粒体功能都很重要。人们普遍认为，运动引起的这些变化中的大部分(如果不是全部)是由pGC-1�引起的。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，运动诱导的线粒体变化不需要pGC-1�。此外，线粒体动力学(融合/分裂)在运动反应中改善肌肉功能的作用尚不清楚，其对去除不良和受损线粒体的贡献也未被研究。这些观察表明，我们对运动引起的骨骼肌变化的理解是不完整的。因此，这项建议的总体目标是了解运动和PGC-1如何影响线粒体数量和动力学，以改善肌肉表现。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。这一建议的结果对于我们理解运动在治疗线粒体疾病中的好处具有广泛的意义。其具体目的是：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)确定运动和PGC-1�和�在调节线粒体融合和分裂中的作用；3)测试是否融合/分裂 参与了随着年龄的增长而进行的锻炼带来的显著改善。这位候选人正在贝丝以色列女执事医疗中心(BIDMC)的心血管研究所(CVI)完成博士后培训，BIDMC是哈佛医学院的一家教学医院。他的主要导师是Zoltan Arany博士，医学助理教授，在PGC-1辅活化子、分子生物学和新陈代谢方面拥有丰富的经验。他的合作导师是医学副教授劳里·古德伊尔博士，他是世界著名的运动生理学和骨骼肌专家。候选人的长期职业目标是在运动生理学和线粒体动力学方面建立独立的研究计划。为了实现这一目标，他制定了一系列短期目标，旨在增强他对线粒体功能、骨骼肌、运动生理学和先进成像技术的知识，这些将在他的导师监督团队和全面的职业发展计划的帮助下进行。该提案的结果将在3-5年内作为R系列提案(如R01)的基础和初步数据。

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.