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: 10237380
• 负责人: Clara Bien Peek
• 金额: $ 40.6万
• 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/10237380
• 关键词: ARNTL gene; Ablation; Acute; Address; Affect; Animal Model; Animals; Cardiometabolic Disease; Cells; Circadian Dysregulation; Circadian Rhythms; Collection; Consumption; Contracts; Coupling; Data; Diet; Disease; Disease Resistance; Epidemiology; Exercise; Exercise Physiology; Exposure to; Fasting; Feeding behaviors; Functional disorder; Gene Expression; Genes; Genetic; Genetic Transcription; Genomics; Glucose; Glycolysis Induction; 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; 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; XCL1 gene; 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.

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