Regulation of Skeletal Muscle Mitochondrial Quality Control Parameters and Systemic Metabolism

项目总结 肥胖和II型糖尿病(T2D)与骨骼肌线粒体功能障碍有关。当前 药物干预在一定程度上限制了它们恢复正常线粒体功能的能力 由于治疗目标有限。到目前为止，运动是许多代谢疾病最著名的治疗方法。 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，调控线粒体质量的分子途径并不是 完全理解。过氧化物酶体增殖物激活受体-1(PGC-1)的成员 转录辅活化子家族被认为对线粒体很重要，并最终 肌肉功能。Pgc-1α亚型被认为是家庭成员对大多数 并不是所有的，都是锻炼带来的有益变化。然而，我们观察到pgc-1α在 骨骼肌不影响线粒体参数的适应性变化。此外，我们还 研究表明，同时缺失骨骼肌中的pGC-1α和pGC-1β对 线粒体功能，但不是线粒体含量，这表明线粒体质量控制存在差异 参数。这些数据表明，其他参与者也参与了线粒体功能的调节和 骨骼肌中的数字。我们相信，被广泛研究的家庭成员PGC-1与 辅活剂(PRC)就是这一因素。此外，PRC在骨骼肌中扮演的角色尚不清楚。此外， 运动诱发PRC和全身杂合子缺失的观察 有代谢功能障碍，强烈表明它在运动反应中发挥作用。因此，总体来说， 这项建议的目的是了解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、基于细胞的分析和线粒体分析我们将尝试解决这一非常重要的问题。 这一建议的结果对我们理解骨骼代谢紊乱有广泛的意义。 以及PRC在骨骼肌中的作用。具体目标是：1.确定中华人民共和国在以下领域的角色 骨骼肌线粒体质量控制，无论是在基线训练还是运动训练中；审问 饮食诱导的代谢失衡对成人骨骼肌线粒体质量控制的影响 获得性线粒体氧化能力缺乏；为了证明运动训练保留了 氧化能力受损的成人骨骼肌中线粒体的质量控制。这项建议将有助于 提供我们对骨骼肌中的PRC及其贡献的急需的见解 代谢功能障碍。

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.