Clock Control of Muscle Glucose Metabolism and HIF Activity

项目总结： 尽管最近在揭示生物钟在心脏代谢性疾病和类型中的作用方面取得了进展- 2糖尿病，我们对营养和昼夜节律转录调节的理解仍然存在差距 以特定于组织的方式在24小时周期内协调对环境刺激的反应。 我们最近发表的研究发现了骨骼肌之间新的相互作用 生物钟和营养敏感的缺氧诱导因子(HIF)转录途径。 具体地说，我们的工作表明：(I)昼夜节律转录因子调节缺氧性hif1α 肌肉肌管的激活和厌氧糖酵解，(Ii)肌肉生物钟调节 全基因组低氧转录，以及(Iii)生物钟建立一天中的时间依赖 骨骼肌对运动诱导的缺氧诱导因子激活的反应。总的来说，这些研究揭示了 低氧诱导因子与昼夜节律途径的偶联以产生节律适应 对缺氧性压力。然而，目前还不清楚这种偶联如何调节转录和 代谢流量，以及体内昼夜节律紊乱是否损害HIF依赖的代谢 功能，如在运动和饮食诱导的情况下肌肉中葡萄糖的处理 肥胖。我们目前提议的研究将利用一系列创新的模型和技术来建立 根据我们目前的发现，了解低氧和昼夜节律转录之间的相互作用 基因组、营养信号和整个动物生理水平的途径。总的来说，这些 研究将促进我们对生物钟在肌肉代谢中的作用的理解 功能和疾病。

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.