Clock Control of Muscle Glucose Metabolism and HIF Activity

肌肉葡萄糖代谢和 HIF 活性的时钟控制

• 批准号: 10633102
• 负责人: Clara Bien Peek
• 金额: $ 39.64万
• 依托单位: NORTHWESTERN UNIVERSITY AT CHICAGO
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-08-12 至 2025-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10633102
• 关键词: ARNTL gene; ATAC-seq; Ablation; Acute; Address; Affect; Animal Model; Animals; Cardiometabolic Disease; Cells; ChIP-seq; Circadian Dysregulation; Circadian Rhythms; Collection; Contracts; Coupling; Darkness; Data; Diet; Disease; Disease Resistance; Energy consumption; Epidemiology; Exercise; Exercise Physiology; Exposure to; Fasting; Feeding behaviors; Functional disorder; Gene Expression; Genes; Genetic; Genetic Transcription; Genomics; Glucose; Glycolysis; Goals; HIF1A gene; Hour; Human; Hypoxia; Hypoxia Inducible Factor; Hypoxia-Inducible Factor Pathway; Impairment; In Vitro; Incidence; Insulin Resistance; Isotope Labeling; Knockout Mice; Knowledge; Light; Link; Metabolic; Metabolic Diseases; Metabolism; Mitochondria; Modeling; Molecular; Mus; Muscle; Muscle Fibers; Mutant Strains Mice; Non-Insulin-Dependent Diabetes Mellitus; Nutrient; Obesity; Pathway interactions; Periodicity; Persons; Physiological; Predisposition; Process; Production; Public Health; Publishing; RNA; Respiration; Rest; Role; Signal Transduction; Skeletal Muscle; Sleep; Sleep Wake Cycle; Stimulus; Strenuous Exercise; Stress; Techniques; Testing; Time; Tissues; Variant; Work; anaerobic glycolysis; blood glucose regulation; circadian; circadian pacemaker; diet and exercise; diet-induced obesity; feeding; genome-wide; glucose disposal; glucose metabolism; in vivo; innovation; insight; molecular clock; novel; response; skeletal muscle wasting; transcription factor; uptake

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.

项目摘要： 尽管最近在揭示了昼夜节律中时钟在心脏代谢疾病和类型中的作用方面取得了进步 2个糖尿病，我们对营养和昼夜节律调节剂的理解仍然存在差距 以组织特异性方式协调对24小时周期环境刺激的反应。 我们最近发表的研究发现了骨骼肌肉之间的新型相互作用 昼夜节律时钟和营养敏感的缺氧诱导因子（HIF）转录途径。 具体而言，我们的工作表明（i）昼夜节律转录因子调节低氧HIF1α 肌肉肌管中的激活和厌氧性糖酵解，（ii）肌肉昼夜节律调节 全基因组缺氧转录，（iii）昼夜节律时钟建立了依赖时间 对运动引起的骨骼肌HIF激活的反应。这些研究共同揭示了 低氧诱导因子和昼夜节律的耦合，以产生节奏适应 低氧应激。但是，目前尚不清楚这种耦合如何调节转录和 代谢通量，以及体内昼夜节律中断是否会损害HIF依赖性代谢 在运动和饮食引起的背景下，诸如肌肉中的葡萄糖处置之类的功能 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来构建 根据我们目前的发现，了解缺氧和昼夜节律之间的相互作用 基因组，营养信号和全动物生理水平的途径。总体而言，这些 研究将促进我们对昼夜节律在肌肉代谢中的作用的理解 功能和疾病。