Regulation of Skeletal Muscle Mitochondrial Quality Control Parameters and Systemic Metabolism

骨骼肌线粒体质量控制参数和全身代谢的调节

• 批准号: 9905516
• 负责人: Glenn Cameron Rowe
• 金额: $ 29.7万
• 依托单位: UNIVERSITY OF ALABAMA AT BIRMINGHAM
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-05-01 至 2022-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9905516
• 关键词: Address; Adherence; Adult; Affect; Attenuated; Biogenesis; Biological; Biological Assay; Cells; Clinical; Data; Development; Diet; Etiology; Exercise; Family; Family member; Gene Expression; Genetic Models; Goals; Heterozygote; High Fat Diet; Human; Impairment; Intervention; Mediating; Metabolic; Metabolic Diseases; Metabolic dysfunction; Metabolism; Mitochondria; Mitochondrial Diseases; Molecular; Mus; Muscle; Muscle Mitochondria; Muscle function; Non-Insulin-Dependent Diabetes Mellitus; Obesity; Outcome; PGC-1 protein; PPAR gamma; Pathologic; Pathway interactions; Patients; Performance; Pharmacologic Substance; Physiological; Play; Protein Isoforms; Publishing; Quality Control; Regulation; Research; Rodent; Role; Skeletal Muscle; Testing; Therapeutic; Transcription Coactivator; base; clinically significant; exercise training; fatty acid oxidation; glucose uptake; improved; innovation; insight; knock-down; loss of function; member; mitochondrial dysfunction; new therapeutic target; novel; overexpression; preservation; prevent; response; sedentary; therapeutic target

PROJECT SUMMARY Obesity and type II diabetes (T2D) is associated with skeletal muscle mitochondrial dysfunction. Current pharmaceutical interventions have been limited in their ability to restore normal mitochondrial function, in part due to limited therapeutic targets. To date, exercise is the best-known treatment for many of these metabolic diseases. The positive effects of exercise are largely considered to be the result of both the quality control and functionality of mitochondria. However, the molecular pathways regulating mitochondria quality control is not fully understood. Members of the peroxisome proliferator-activated receptor gamma coactivator-1 (PGC-1) family of transcriptional coactivators have been identified as being important to mitochondria and ultimately muscle function. The PGC-1α isoform has been credited with being the family member responsible for most, if not all, of beneficial changes in response to exercise. However, we observed that deletion of PGC-1α in skeletal muscle does not affect the adaptive changes in mitochondrial parameters. Moreover, we have also shown that simultaneously deleting both PGC-1α and PGC-1β in skeletal muscle have profound effect on mitochondrial function, but not mitochondrial content suggesting differences in mitochondrial quality control parameters. These data suggest that other players are involved in the regulation of mitochondrial function and number in skeletal muscle. We are confident that the much-understudied family member PGC-1 related coactivator (PRC) is this factor. In addition, the role PRC plays in skeletal muscle is unknown. Furthermore, the observation that PRC is induced in response to exercise and that whole body heterozygote for PRC deletion have a metabolic dysfunction, suggests strongly it plays a role in the exercise response. Therefore, the overall objective of this proposal is to understand the role PRC plays in skeletal muscle with regards to mitochondrial quality control and whole-body systemic metabolism. Using genetic models, diet induced and exercise paradigms, cell-based and mitochondrial assays we will attempt to address this very important question. Results from this proposal have broad implications for our understanding of metabolic disorders in skeletal muscle as well as the role of PRC in skeletal muscle. The specific aims are to: 1.) to define the role of PRC in skeletal muscle mitochondrial quality control, both during baseline and exercise training; 2.) to interrogate the effect of diet-induced metabolic imbalance on mitochondrial quality control in adult skeletal muscle with acquired mitochondrial oxidative capacity deficiency; and 3.) to demonstrate that exercise training preserves mitochondrial quality control in adult skeletal muscle with impaired oxidative capacity. This proposal will to provide much needed insights into our understanding of PRC in skeletal muscle and its contribution to metabolic dysfunction.

项目摘要 肥胖和II型糖尿病（T2D）与骨骼肌线粒体功能障碍有关。当前的 药物干预措施的恢复正常线粒体功能的能力受到限制 由于治疗靶标有限。迄今为止，运动是其中许多代谢的最著名治疗方法 疾病。运动的积极影响在很大程度上被认为是质量控制和 线粒体的功能。但是，调节线粒体质量控制的分子途径不是 完全理解。过氧化物增生剂激活受体伽马共振剂1（PGC-1）的成员 转录共激活因子家族已被确定为对线粒体和最终 肌肉功能。 PGC-1α同工型被认为是对大多数家庭成员负责的，如果 并非全部，有益于锻炼。但是，我们观察到PGC-1α在 骨骼肌不会影响线粒体参数的自适应变化。而且，我们也 表明骨骼肌中同时删除PGC-1α和PGC-1β对 线粒体功能，但不提示线粒体含量提示线粒体质量控制的差异 参数。这些数据表明，其他参与者参与了线粒体功能的调节和 骨骼肌的数量。我们相信，备受理解的家庭成员PGC-1与 共激活因子（PRC）是这个因素。此外，PRC在骨骼肌中的作用尚不清楚。此外， 观察到PRC是响应于运动的诱导的，而全身杂合子则用于PRC缺失 具有代谢功能障碍，表明它在运动反应中起着作用。因此，整体 该建议的目的是了解PRC在线粒体方面的作用 质量控制和全身全身代谢。使用遗传模型，饮食诱导和运动 我们将尝试解决这个非常重要的问题。 该提案的结果对我们对骨骼代谢疾病的理解具有广泛的影响 肌肉以及中国在骨骼肌中的作用。具体目的是：1。）定义中国在 在基线和运动训练期间，骨骼肌线粒体质量控制； 2.）审问 饮食引起的代谢失衡对成人骨骼肌线粒体质量控制的影响 获得的线粒体氧化能力缺乏； 3.）证明运动训练保留 氧化物能力受损的成年骨骼肌的线粒体质量控制。该建议将 提供急需的见解，以了解我们对骨骼肌中的中国的理解及其对 代谢功能障碍。