Exercise-Induced Mitochondrial Biogenesis

描述(由申请人提供)：骨骼肌通过激活多个信号通路来应对收缩活动的持续增加而进行适应。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*共激活物-U(PGC-U)的表达在适应中起着关键作用。因此，对PGC-U基因调控的深入了解将有助于我们更好地理解骨骼肌适应的分子机制。我们以前在活体小鼠的骨骼肌中开发了一种新的启动子活性的成像分析，并且已经证明收缩活动诱导的骨骼肌中PGC-U基因的转录依赖于PGC-U启动子上的肌细胞增强因子2(MEF2)结合位点和环状AMP反应元件(CRE)。到目前为止，一些功能获得遗传学方法的发现表明，潜在上游调控因子的活性形式的肌肉特异性过表达可以增强PGC-U蛋白的表达；然而，还没有研究在整个动物模型中使用功能丧失方法来描述上游调控因子和PGC-U启动子之间的直接相互作用。我们假设，直接与MEF2和Cre结合位点相互作用的转录因子以及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。其具体目的是：1.明确MEF2和Cre序列元件在收缩活性诱导的活体小鼠PGC-U启动子活性中的功能作用。2.确定收缩活性诱导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。这项研究的发现可能会促进改善骨骼肌功能和治疗与骨骼肌疾病相关的疾病的创新方法。

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.