Clock Control of Muscle Glucose Metabolism and HIF Activity

项目概要： 尽管最近在揭示生物钟在心脏代谢疾病和型糖尿病中的作用方面取得了进展， 2型糖尿病，在我们理解营养和昼夜转录调节因子如何 以组织特异性方式协调24小时周期内对环境刺激的反应。 我们最近发表的研究揭示了骨骼肌之间的新的相互作用 生物钟和营养敏感缺氧诱导因子（HIF）转录途径。 具体而言，我们的工作表明：（i）昼夜转录因子调节缺氧HIF 1 α， 激活和无氧糖酵解在肌肉肌管，（ii）肌肉昼夜节律钟调节 全基因组低氧转录，和（iii）生物钟建立一个依赖于一天中的时间 对运动诱导的骨骼肌中HIF激活的反应。总的来说，这些研究表明 缺氧诱导因子和昼夜节律通路的偶联，以产生节律性适应 缺氧压力。然而，目前还不清楚这种偶联如何调节转录， 代谢通量，以及体内昼夜节律破坏是否损害HIF依赖性代谢 功能，如在运动和饮食诱导的情况下肌肉中的葡萄糖处置 肥胖我们目前提出的研究将利用一系列创新的模型和技术， 根据我们目前的发现，了解缺氧和昼夜转录之间的相互作用， 在基因组、营养信号传导和整个动物生理水平上的途径。总的来说，这些 研究将促进我们对生物钟在肌肉代谢中作用的理解 功能与疾病

PROJECT SUMMARY: Despite recent advances in uncovering the role of circadian clocks in cardiometabolic disease and type- 2 diabetes, a gap remains in our understanding of how nutrient and circadian transcriptional regulators coordinate responses to environmental stimuli across the 24-hour cycle in a tissue-specific manner. Our recently published studies uncovered novel reciprocal interactions between the skeletal muscle circadian clock and the nutrient-sensitive hypoxia-inducible factor (HIF) transcription pathway. Specifically, our work demonstrated that (i) circadian transcription factors regulate hypoxic HIF1α activation and anaerobic glycolysis in muscle myotubes, (ii) the muscle circadian clock regulates genome-wide hypoxic transcription, and (iii) the circadian clock establishes a time-of-day dependent response to exercise-induced HIF activation in skeletal muscle. Collectively, these studies reveal coupling of the hypoxia-inducible factor and circadian pathways in order to produce rhythmic adaptation to hypoxic stress. However, it is still unclear how this coupling acts to regulate transcription and metabolic flux, and whether in vivo circadian disruption impairs HIF-dependent metabolic functions, such as glucose disposal in muscle in the context of exercise and diet-induced obesity. Our present proposed studies will utilize an array of innovative models and techniques to build upon our current findings to understand the interplay between hypoxic and circadian transcriptional pathways at the genomic, nutrient-signaling, and whole-animal physiological levels. Overall, these studies will advance our understanding of the role of circadian clocks in muscle metabolic function and disease.