Regulation of Muscle Protein Phenotype in Humans with Obesity

肥胖人群肌肉蛋白表型的调节

• 批准号: 10361952
• 负责人: Christos S Katsanos
• 金额: $ 6.2万
• 依托单位: ARIZONA STATE UNIVERSITY-TEMPE CAMPUS
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-07-15 至 2024-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10361952
• 关键词: Acute; Adult; Aerobic Exercise; Amino Acids; Biological; Biological Process; Biology; Characteristics; Clinical; Clinical Research; Complex; Coupling; Data; Defect; Eukaryotic Initiation Factor-4F; Exercise; Fiber; Gene Expression; Genes; Genetic Transcription; Goals; Health; Homeostasis; Human; Impairment; Intervention; Investigation; Knowledge; Life; Link; Maintenance; Measures; Messenger RNA; Metabolic; Metabolism; Molecular; Molecular Biology Techniques; Muscle; Muscle Fibers; Muscle Mitochondria; Muscle Proteins; Myosin Heavy Chains; Obesity; Outcome; Phenotype; Physiological; Plasma; Population; Process; Production; Protein Biosynthesis; Protein Isoforms; Proteins; Proteome; Regulation; Research; Resistance; Signal Transduction; Skeletal Muscle; Skeletal Muscle Myosins; Slow-Twitch Muscle Fibers; Stimulus; Testing; Thinness; Tracer; Transcription Process; Translations; United States; differential expression; functional outcomes; glucose uptake; improved; insight; insulin sensitivity; mRNA Expression; muscle metabolism; novel; obese person; programs; protein complex; protein expression; proteostasis; response; stable isotope; tool; weight loss intervention

Project Summary/Abstract Obesity is increasing in the developed world, and more than one-third of the adult population (35%) in the United States are classified as obese. When compared to lean humans, humans with obesity demonstrate differential expression of proteins in skeletal muscle. Differential expression of skeletal muscle myosin heavy chain (MHC) protein isoforms, which collectively determine the MHC proteome in skeletal muscle, is a hallmark of distorted muscle proteome in humans with obesity. The content of the MHC-I isoform is characteristically low, whereas that of MHC-IIx is high, in skeletal muscle of humans with obesity, resulting in an unfavorable muscle MHC proteome phenotype that has been consistently linked to obesity-associated adverse metabolic and functional outcomes. These MHC-specific proteome alterations in muscle of humans with obesity are resistant to weight-loss interventions, indicating an apparent inflexibility in modifying the MHC proteome in muscle of humans with obesity, and with life-long physiological and clinical implications. We will determine rates of synthesis and breakdown of the overall proteome in skeletal muscle of humans with obesity and lean controls, along with relevant molecular mechanisms regulating these processes in muscle. We will focus specifically on the rates of synthesis and breakdown of MHC isoforms, as well as gene expression of the MHC isoforms. That way, we will be able to obtain a deeper insight on the biology that sustains the unfavorable MHC proteome phenotype in muscle of humans with obesity. A prerequisite for muscle MHC proteome remodeling in humans with obesity is an increase in the content of the MHC-I isoform, which is physiologically achieved by increase in the rate of synthesis of MHC-I. Acute aerobic exercise provides the muscle with a stimulus to increase MHC-I transcription, while acute increase in plasma amino acids is a powerful signal to upregulate overall protein translation in muscle. Consequently, by employing acute aerobic exercise and increase in plasma amino acids as investigational tools to target biological processes of transcription and translation, respectively, that regulate the rate of synthesis of MHC-I in muscle we expect to understand the underlying biological mechanisms responsible for distorted MHC proteome in muscle of humans with obesity. Overall, these studies will investigate the mechanistic underpinnings responsible for disrupted muscle proteome homeostasis in skeletal muscle of humans with obesity. Findings from the proposed studies will provide an understanding particularly of the factors that sustain unfavorable MHC proteome in muscle of humans with obesity. Furthermore, these findings may provide novel targets for interventions that can favorably remodel the muscle proteome in obesity to improve metabolism and function in skeletal muscle of humans with obesity.

项目总结/摘要 在发达国家，肥胖症正在增加，在发达国家，超过三分之一的成年人口（35%） 美国被列为肥胖。与瘦人相比，肥胖的人表现出 骨骼肌中蛋白质的差异表达。骨骼肌肌球蛋白重链的差异表达 在骨骼肌中，MHC蛋白质组的共同决定因素是一种标志性的MHC蛋白质亚型， 肌肉蛋白质组的扭曲。MHC-I同种型的含量特征性地低， 而MHC-IIx在肥胖症患者的骨骼肌中的表达很高， MHC蛋白质组表型一直与肥胖相关的不良代谢和 功能性成果。这些MHC特异性蛋白质组的改变，在人类的肌肉与肥胖是抵抗 减肥干预，表明在修改肌肉中的MHC蛋白质组的明显的可操作性， 人类肥胖，并与终身的生理和临床意义。 我们将确定人类骨骼肌中整体蛋白质组的合成和分解速率 与肥胖和瘦对照，沿着调节肌肉中这些过程的相关分子机制。 我们将特别关注MHC异构体的合成和分解速率，以及基因表达 MHC异构体。这样，我们将能够更深入地了解维持生命的生物学。 肥胖症患者肌肉中不利的MHC蛋白质组表型。肌肉MHC的先决条件 肥胖症患者的蛋白质组重塑是MHC-I同种型含量的增加， 通过增加MHC-I的合成速率在生理上实现。急性有氧运动提供了 肌肉刺激增加MHC-I转录，而血浆氨基酸的急性增加是一个强大的 信号以上调肌肉中的整体蛋白质翻译。因此，通过采用急性有氧运动， 和血浆氨基酸的增加作为靶向转录的生物过程的研究工具， 翻译，分别调节肌肉中MHC-I的合成速率，我们希望了解 肥胖症患者肌肉中MHC蛋白质组扭曲的潜在生物学机制。 总的来说，这些研究将调查负责破坏肌肉的机械基础 肥胖症患者骨骼肌中蛋白质组的稳态。拟议研究的结果将 提供了一个理解，特别是维持不利的MHC蛋白质组在人类肌肉的因素 肥胖症此外，这些发现可能为干预提供新的靶点， 肥胖症中的肌肉蛋白质组，以改善肥胖症患者骨骼肌的代谢和功能。