Circadian clock and temporal control in nutrient metabolism

项目摘要 生物钟对新陈代谢途径进行时间控制，它的中断会导致胰岛素抵抗。 还有肥胖症。骨骼肌在营养代谢和蛋白质动态平衡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。 尽管对糖和脂代谢的昼夜节律进行了广泛的研究，但目前 关于决定肌肉质量的蛋白质新陈代谢中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不清楚。我们已经发现了一种新颖的时钟驱动的 非摄食诱导对骨骼肌PI3K-Akt-mTORC1信号的时间调控 激活。令人惊讶的是，模仿轮班的时钟紊乱会导致进行性肌肉萎缩 伴有PI3K-Akt信号受损和蛋白质周转增加。此外，机械论研究 揭示了Insulin/IGF-1-PI3K-Akt-mTor信号级联的昼夜时钟转录控制。这些 研究结果与先前的研究一起支持这样一种假设，即肌肉内在的时钟赋予时间 控制PI3K-Akt-mTOR级联反应以驱动蛋白质代谢和胰岛素敏感性，及其机制 是昼夜节律紊乱导致的肌肉萎缩和胰岛素抵抗的基础。这个项目的首要目标是 是全面定义肌肉营养中新发现的Clock-PI3K-Akt-mTor调节轴 动态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 用多重组学方法全面定义与疾病相关的分子机制 Clock-Akt-mTor调节轴在蛋白质代谢、胰岛素敏感性和蛋白质代谢中的生理学意义 维持肌肉质量。更重要的是，我们建议测试遗传和药物时钟的增加。 干预措施，以抵消由时钟干扰引起的肌肉合成代谢和代谢缺陷。其结果是 这一建议可能揭示导致骨质疏松症代谢能力受损的昼夜节律病因，并提供 时钟定向干预的机制基础。

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.