Circadian clock and temporal control in nutrient metabolism

昼夜节律时钟和营养代谢的时间控制

• 批准号: 10754101
• 负责人: Ke Ma
• 金额: $ 45.38万
• 依托单位: BECKMAN RESEARCH INSTITUTE/CITY OF HOPE
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-09-01 至 2027-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10754101
• 关键词: ARNTL gene; Ablation; Aging; Atrophic; Attenuated; Automobile Driving; Autophagocytosis; Cells; ChIP-seq; Circadian Dysregulation; Circadian desynchrony; Coupled; Defect; Etiology; FRAP1 gene; Functional disorder; Genetic; Genetic Models; Genetic Transcription; Glucose; Goals; Growth; Homeostasis; Impairment; Insulin; Insulin Resistance; Intervention; Knowledge; Label; Life Style; Link; Lipids; Maintenance; Mediating; Metabolic; Metabolic Pathway; Metabolism; Modeling; Modernization; Molecular; Muscle; Muscle Development; Muscle Fibers; Muscle Proteins; Muscular Atrophy; Nutrient; Obesity; Outcome; Output; PIK3CG gene; Pathway interactions; Periodicity; Physiological; Play; Prevalence; Protein Biosynthesis; Proteins; Proteomics; Regulation; Research; Research Support; Resistance; Role; Signal Transduction; Skeletal Muscle; Stimulus; Testing; Therapeutic; Time; Transcription Coactivator; Transcriptional Regulation; Translations; Wasting Syndrome; circadian; circadian pacemaker; circadian regulation; feeding; gain of function; genetic testing; glucose metabolism; improved; insulin sensitivity; lipid metabolism; loss of function; mTOR Signaling Pathway; metabolomics; mouse model; multiple omics; muscle form; nobiletin; novel; nutrient metabolism; pharmacologic; prevent; protein degradation; protein metabolism; proteostasis; response; sarcopenia; sarcopenic obesity; sensor; shift work; transcriptomics

Project Summary The circadian clock confers temporal control to metabolic pathways, and its disruption leads to insulin resistance and obesity. Skeletal muscle plays a critical role in nutrient metabolism and protein homeostasis. We and others demonstrated that the muscle-intrinsic clock regulates skeletal muscle development, growth, and metabolism. Despite the extensive studies of circadian regulation in glucose and lipid metabolism, there is a current knowledge gap regarding clock function in protein metabolism that determines muscle mass. In addition, although circadian misalignment is prevalent in a modern lifestyle, potential circadian etiologies underlying muscle wasting and impaired metabolic capacity remains unknown. We have identified a novel clock-driven temporal control of PI3K-Akt-mTORC1 signaling in skeletal muscle that is independent of feeding-induced activation. Surprisingly, clock disruption mimicking shiftwork resulted in progressive muscle atrophy accompanied with impaired PI3K-Akt signaling and elevated protein turnover. Furthermore, mechanistic studies revealed circadian clock transcriptional control of the Insulin/Igf-1-PI3K-Akt-mTOR signaling cascade. These findings, together with prior research support a hypothesis that that the muscle-intrinsic clock confers temporal control in PI3K-Akt-mTOR cascade to drive protein metabolism and insulin sensitivity, and this mechanism underlies circadian disruption-induced muscle atrophy and insulin resistance. The overarching goal of this project is to comprehensively define this newly discovered clock-PI3K-Akt-mTOR regulatory axis in muscle nutrient homeostasis and muscle mass regulation. Specifically, we will leverage our unique clock modulation models with multi-omics approaches to comprehensively define the molecular mechanisms responsible for and the physiological significance of the clock-Akt-mTOR regulatory axis in protein metabolism, insulin sensitivity and muscle mass maintenance. More importantly, we propose to test genetic and pharmacological clock-augmenting interventions to counteract muscle anabolic and metabolic deficits induced by clock disruption. The outcome of this proposal may uncover a circadian etiology underlying impaired metabolic capacity in sarcopenia and provide the mechanistic basis for clock-targeting interventions.

项目概要 生物钟赋予代谢途径时间控制，其破坏会导致胰岛素抵抗 和肥胖。骨骼肌在营养代谢和蛋白质稳态中起着至关重要的作用。我们和其他人 证明肌肉内在时钟调节骨骼肌的发育、生长和新陈代谢。 尽管对葡萄糖和脂质代谢的昼夜节律调节进行了广泛的研究，但目前仍存在 关于决定肌肉质量的蛋白质代谢时钟功能的知识差距。此外， 尽管昼夜节律失调在现代生活方式中很普遍，但潜在的昼夜节律病因 肌肉萎缩和代谢能力受损仍然未知。我们已经确定了一种新颖的时钟驱动 骨骼肌中 PI3K-Akt-mTORC1 信号传导的时间控制独立于进食诱导 激活。令人惊讶的是，模仿轮班工作的时钟中断会导致进行性肌肉萎缩 伴随着 PI3K-Akt 信号传导受损和蛋白质周转率升高。此外，机理研究 揭示了胰岛素/Igf-1-PI3K-Akt-mTOR 信号级联的生物钟转录控制。这些 研究结果与之前的研究一起支持了一个假设，即肌肉内在时钟赋予时间 控制 PI3K-Akt-mTOR 级联以驱动蛋白质代谢和胰岛素敏感性，并且该机制 是昼夜节律紊乱引起的肌肉萎缩和胰岛素抵抗的基础。该项目的总体目标 就是要全面定义这个新发现的肌肉营养中的时钟-PI3K-Akt-mTOR调节轴 体内平衡和肌肉质量调节。具体来说，我们将利用我们独特的时钟调制模型 多组学方法全面定义负责的分子机制和 时钟-Akt-mTOR 调节轴在蛋白质代谢、胰岛素敏感性和 肌肉质量维持。更重要的是，我们建议测试遗传和药理学时钟增强 采取干预措施来抵消生物钟干扰引起的肌肉合成代谢和代谢缺陷。结果 该提议可能揭示肌肉减少症代谢能力受损的昼夜节律病因，并提供 时钟靶向干预的机制基础。