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

运动和骨骼肌 PGC-1 共激活剂对线粒体的调节

• 批准号: 9124710
• 负责人: Glenn Cameron Rowe
• 金额: $ 12.45万
• 依托单位: UNIVERSITY OF ALABAMA AT BIRMINGHAM
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-02-13 至 2018-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9124710
• 关键词: Address; Affect; Age; Aging; Biogenesis; Biological Assay; Cardiovascular system; DNA Sequence Alteration; Data; Development Plans; Diabetes Mellitus; Disease; Elderly; Electron Microscopy; Evaluation; Event; Exercise; Exercise Physiology; Family; Foundations; Gene Expression; Genetic Models; Goals; Green Fluorescent Proteins; Histology; Image; Imaging technology; Institutes; Intervention; Israel; Knowledge; Label; Longevity; Mediating; Mediator of activation protein; Medical center; Medicine; Mentors; Mentorship; Metabolism; Mitochondria; Mitochondrial Diseases; Modeling; Molecular; Molecular Biology; Monitor; Mus; Muscle; Muscle Mitochondria; Muscle function; Muscular Atrophy; PPAR gamma; Pathway interactions; Performance; Physiological; Physiology; Premature aging syndrome; Process; Proteins; Quality Control; Quality of life; Regulation; Research; Respiration; Role; Series; Skeletal Muscle; Teaching Hospitals; Testing; Time; Tissues; Transcription Coactivator; Ursidae Family; Work; career; career development; cellular imaging; design; experience; gain of function; improved; in vitro Assay; in vivo; in vivo Model; insight; loss of function; medical schools; member; mid-career faculty; mitochondrial DNA mutation; mitochondrial dysfunction; mouse model; muscular system; novel; post-doctoral training; professor; programs; receptor; response; tool; two-photon

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.

描述（适用提供）：锻炼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的理解很少。过氧化物组增殖物激活的受体伽马共振剂-1（PGC-1）共激活剂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。普遍建议，PGC-1负责大多数（如果不是全部）响应于运动的变化。但是，我们观察到PGC-1的缺失不影响线粒体参数的自适应变化。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/裂变）在响应运动中改善肌肉功能中的作用尚不清楚，并且未研究其对去除不良和损坏的线粒体的贡献。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，该提案的总体目的是了解运动和PGC-1如何影响线粒体的数量和动态以改善肌肉性能。利用遗传模型，细胞成像和线粒体的阿萨斯，我们将尝试解决这些非常重要的问题。该提案的结果对我们了解运动对线粒体疾病的益处的理解具有广泛的影响。具体目的是：1）确定PGC-1和控制运动诱导的线粒体生物发生的贡献； 2）确定运动和PGC-1的作用以及控制线粒体融合和裂变的作用； 3）测试是否融合/裂变 参与了随着衰老的锻炼而征服的戏剧性改进。候选人正在哈佛医学院教学医院的贝丝以色列女执事医疗中心（BIDMC）完成他在心血管研究所（CVI）的博士后培训。他的主要心态是医学助理教授Zoltan Arany博士，在PGC-1共激活剂，分子生物学和代谢方面拥有丰富的经验。他的同事是医学副教授Laurie Goodyear博士，是世界知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，他创建了一系列的短期目标，旨在增强他对线粒体功能，骨骼肌肉，运动生理学和先进成像技术的了解，这将由他的Mentalship监督团队和全面的职业发展计划准备。该提案的结果将作为R系列提案（例如3 - 5年内R01）的基础和初步数据。