Regulation of Muscle Protein Phenotype in Humans with Obesity

项目摘要/摘要 骨骼肌肌球蛋白重链(MHC)蛋白亚型的扭曲表达，这些蛋白共同 确定MHC蛋白质组，是肥胖者肌肉蛋白质组改变的标志。最多的 这一现象的显著特征是慢的MHC-I亚型的含量减少，这是 用于测定I型肌纤维的含量。I型肌肉纤维的特征是容量增加 对于葡萄糖摄取，与II型纤维不同，将它们对胰岛素的敏感性保持在不利的 与肥胖相关的代谢环境。增加了骨骼肌中I型纤维的含量，因此 肌肉的良好代谢作用，需要增加肌肉中MHC-I的表达。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 骨骼肌的表型。我们试图确定维持扭曲的MHC的潜在生物学 肥胖人群骨骼肌蛋白质组研究。 我们将评估肥胖和瘦身对照人群骨骼肌的总蛋白质周转率，以及 特别关注MHC亚型。我们将确定MHC亚型的基因表达和 激活I型肌纤维程序以获得更深层次洞察的相关分子因素 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 骨骼肌中与MHC基因表达相关的转录和翻译的靶生物学过程。 最终，我们的发现将提供对不利的MHC蛋白质组的机制的理解。 肥胖者骨骼肌纤维类型表型。这些发现将对我们的知识有所帮助 关于可以有利地重塑肌肉蛋白质组和改善肌肉代谢的分子靶点 肥胖的人类。

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.