Exercise-Induced Mitochondrial Biogenesis

描述（由申请方提供）：通过激活多种信号传导途径，骨骼肌对收缩活动持续增加做出适应性反应。越来越多的证据表明，运动诱导的过氧化物酶体增殖物激活受体 * 共激活因子-U（PGC-U）的表达在适应中起着关键作用。因此，深入了解PGC-U基因调控将提高我们对骨骼肌适应的分子机制的理解。我们以前已经开发了一种新的成像分析在活小鼠骨骼肌中的启动子活性，并已表明，收缩活动诱导的PGC-U基因转录在骨骼肌中依赖于两个肌细胞增强因子2（MEF 2）的结合位点和环AMP反应元件（CRE）的PGC-U启动子。迄今为止，一些研究结果与获得的功能遗传学方法表明，PGC-U蛋白的表达可以增强肌肉特异性过表达的活性形式的潜在上游调控因子，但是，一直没有研究描绘的上游调控因子和PGC-U启动子之间的直接相互作用，使用功能丧失的方法在整个动物模型。我们推测，直接与MEF 2和CRE结合位点相互作用的转录因子和调节这些转录因子活性的信号分子调节PGC-U转录，以响应体内骨骼肌收缩活性的增加。具体目标是：1.确定MEF 2和CRE序列元件在活体小鼠收缩活性诱导的PGC-U启动子活性中的功能作用。2.确定收缩活性诱导的PGC-U启动子活性所需的转录因子-启动子相互作用。该实验计划包括在我们实验室开发的一种新的体内方法。我们期待着重要的新信息出现。这项研究的结果可能会促进创新方法，以改善骨骼肌功能和治疗与骨骼肌疾病相关的疾病。

DESCRIPTION (provided by applicant): Skeletal muscle undergoes adaptation in response to a sustained increase of contractile activity through activation of multiple signaling pathways. Accumulating evidence suggests that exercise induced-expression of peroxisome proliferator-activated receptor * co-activator-U (PGC-U) plays a pivotal role in the adaptation. Hence, gaining insights into the PGC-U gene regulation will improve our understanding of the molecular mechanism underlying skeletal muscle adaptation. We have previously developed a novel imaging analysis for promoter activity in skeletal muscles in living mice and have shown that contractile activity-induced PGC-U gene transcription in skeletal muscle depends on both the myocyte enhancer factor 2 (MEF2) binding sites and the cyclic AMP response element (CRE) on the PGC-U promoter. To date, several findings with gain-of-function genetic approaches have shown that PGC-U protein expression can be enhanced by muscle-specific overexpression of active forms of potential upstream regulatory factors; however, there has been no studies delineating the direct interactions between the upstream regulatory factor and the PGC-U promoter using loss-of-function approaches in whole animal models. We hypothesize that transcription factors that directly interact with the MEF2 and CRE binding sites and the signaling molecules that modulate the activities of these transcription factors regulate PGC-U transcription in response to increased contractile activity in skeletal muscle in vivo. The specific aims are to: 1. To define the functional role of the MEF2 and CRE sequence elements in contractile activity-induced PGC-U promoter activity in living mice. 2. Determine the transcription factor-promoter interaction that is required for contractile activity-induced PGC-U promoter activity. The experimental plan includes a novel in vivo approach that was developed in our laboratory. We anticipate important new information to emerge. Findings from this research will likely foster innovative approaches to improve skeletal muscle function and treat diseases related to skeletal muscle disorder.