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（T2 D）与骨骼肌线粒体功能障碍有关。电流 药物干预在恢复正常线粒体功能的能力方面受到限制， 由于治疗靶点有限。到目前为止，运动是最有名的治疗许多这些代谢性疾病的方法。 疾病锻炼的积极效果在很大程度上被认为是质量控制和 线粒体的功能。然而，调节线粒体质量控制的分子途径不是 完全理解过氧化物酶体增殖物激活受体γ共激活因子-1（PGC-1） 转录辅激活因子家族已被鉴定为对线粒体重要，并最终 肌肉功能PGC-1α亚型被认为是负责大多数，如果 不是所有的，有益的变化，以回应运动。然而，我们观察到，PGC-1α的缺失， 骨骼肌不影响线粒体参数的适应性变化。此外，我们还 同时删除骨骼肌中的PGC-1α和PGC-1β对 线粒体功能，而不是线粒体含量，表明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， 骨骼肌中的数量。我们相信，研究不足的家庭成员PGC-1相关 辅活化剂（PRC）是该因子。此外，PRC在骨骼肌中的作用尚不清楚。而且 观察到PRC是由运动引起的，并观察到PRC缺失的全身杂合子 有代谢功能障碍，强烈表明它在运动反应中起作用。因此整体 本提案的目的是了解PRC在骨骼肌中与线粒体有关的作用， 质量控制和全身系统代谢。使用遗传模型，饮食诱导和运动 范例，基于细胞和线粒体的测定，我们将试图解决这个非常重要的问题。 这一提议的结果对我们理解骨骼肌中的代谢紊乱具有广泛的意义。 肌肉以及PRC在骨骼肌中的作用。具体目标是：（1）界定中华人民共和国在 在基线和运动训练期间的骨骼肌线粒体质量控制; 2.）询问 饮食诱导代谢失衡对成年人骨骼肌线粒体质量控制影响 获得性线粒体氧化能力缺陷;和3.）来证明运动训练可以 氧化能力受损的成年骨骼肌线粒体质量控制。这项建议将 为我们了解骨骼肌中的PRC及其对 代谢功能障碍