Regulation of Muscle Protein Phenotype in Humans with Obesity

项目概要/摘要 骨骼肌肌球蛋白重链（MHC）蛋白亚型的表达异常， 确定MHC蛋白质组，是肥胖人群肌肉蛋白质组改变的标志。最 其显著特征是缓慢MHC-I亚型含量的特征性减少，这是负责 用于测定I型肌纤维的含量。I型肌纤维的特点是容量增加 对于葡萄糖摄取，与II型纤维相反，在不利的葡萄糖摄取范围内维持其对胰岛素的敏感性。 与肥胖相关的代谢环境。增加骨骼肌中I型纤维的含量， 肌肉中有利的代谢作用需要肌肉中MHC-I的表达增加。重要的是，慢 MHC-I基因驱动决定整个MHC蛋白质组和纤维类型的分子机制 骨骼肌中的表型。我们试图确定维持扭曲的MHC的潜在生物学 肥胖症患者骨骼肌中的蛋白质组。 我们将评估肥胖和瘦对照人群骨骼肌的总体蛋白质周转， 主要集中在MHC亚型上。我们将确定MHC亚型的基因表达， 与激活I型肌纤维编程有关的相关分子因子，以获得更深入的了解 进入维持人类肌肉中不利的MHC蛋白质组/肌纤维表型的生物学， 肥胖我们将采用急性有氧运动和增加血浆氨基酸作为实验工具， 靶向与骨骼肌中MHC基因表达相关的转录和翻译生物学过程。 最终，我们的研究结果将提供对不利的MHC蛋白质组负责的机制的理解 和肥胖症患者骨骼肌中的纤维类型表型。这些发现将有助于我们了解 关于分子靶点，可以有利地重塑肌肉蛋白质组，改善肌肉的代谢， 肥胖的人。

Project Summary/Abstract Distorted expression of isoforms of the skeletal muscle myosin heavy chain (MHC) protein, which collectively determine the MHC proteome, is a hallmark of altered proteome in muscle of humans with obesity. The most striking feature of this is a characteristic reduction in the content of the slow MHC-I isoform, which is responsible for determining the content of Type I muscle fibers. Type I muscle fibers are characterized by increased capacity for glucose uptake, and in contrast to Type II fibers, maintain their sensitivity to insulin within the adverse metabolic environment associated with obesity. Increased content of Type I fibers in skeletal muscle, and thus favorable metabolic effects in muscle, require increased expression of MHC-I in muscle. Importantly, the slow MHC-I gene drives the molecular mechanisms that determine the overall MHC proteome and fiber type phenotype in skeletal muscle. We seek to determine the underlying biology that sustains distorted MHC proteome in skeletal muscle of humans with obesity. We will evaluate overall protein turnover in skeletal muscle of humans with obesity and lean controls, and focus specifically on that of MHC isoforms. We will determine gene expression of the MHC isoforms and associated molecular factors implicated in activating Type I muscle fiber programing to obtain a deeper insight into the biology that sustains the unfavorable MHC proteome/muscle fiber phenotype in muscle of humans with obesity. We will employ acute aerobic exercise and increase in plasma amino acids as experimental tools to target biological processes of transcription and translation related to MHC genes expression in skeletal muscle. Ultimately, our findings will provide an understanding of mechanisms responsible for unfavorable MHC proteome and fiber type phenotype in skeletal muscle of humans with obesity. These findings will advantage our knowledge about molecular targets that can favorably remodel the muscle proteome and improve metabolism in muscle of humans with obesity.