Circadian clock and temporal control in nutrient metabolism

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.