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.

项目概要： 尽管最近在揭示生物钟在心脏代谢疾病和类型中的作用方面取得了进展， 2 型糖尿病，我们对营养和昼夜节律转录调节因子的理解仍存在差距 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新颖的相互作用 生物钟和营养敏感的缺氧诱导因子（HIF）转录途径。 具体来说，我们的工作证明 (i) 昼夜节律转录因子调节缺氧 HIF1α 肌肉肌管中的激活和无氧糖酵解，(ii) 肌肉生物钟调节 全基因组低氧转录，以及（iii）生物钟建立了一天中时间依赖性 总的来说，这些研究揭示了骨骼肌对运动引起的 HIF 激活的反应。 缺氧诱导因子和昼夜节律途径的耦合以产生节律适应 然而，目前尚不清楚这种耦合如何调节转录和 代谢通量，以及体内昼夜节律紊乱是否会损害 HIF 依赖性代谢 功能，例如运动和饮食引起的肌肉中的葡萄糖处理 我们目前提出的研究将利用一系列创新模型和技术来构建。 根据我们目前的研究结果来了解缺氧和昼夜节律转录之间的相互作用 总体而言，这些途径在基因组、营养信号和整个动物生理水平上。 研究将增进我们对生物钟在肌肉代谢中作用的理解 功能和疾病。

项目成果

BMAL1 drives muscle repair through control of hypoxic NAD+ regeneration in satellite cells.

BMAL1 通过控制卫星细胞中缺氧的 NAD 再生来驱动肌肉修复。

• 发表时间: 2022-02-01
• 影响因子: 10.5
• 作者: Zhu, Pei;Hamlish, Noah X;Thakkar, Abhishek Vijay;Steffeck, Adam W T;Rendleman, Emily J;Khan, Nabiha H;Waldeck, Nathan J;DeVilbiss, Andrew W;Martin;Mathews, Thomas P;Chandel, Navdeep S;Peek, Clara B
• 通讯作者: Peek, Clara B