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.

PROJECT NARRATIVE: The widespread incidence of metabolic disease, including obesity and type 2 diabetes mellitus, has emerged as a worldwide public health challenge. Accumulating evidence suggests that susceptibility to these disorders is increased in people who disrupt their daily sleep/wake fasting/feeding cycles, as is often the case for shift or night workers. To advance our understanding of the link between circadian rhythms and metabolism, I propose to pinpoint the molecular mechanisms underlying our recently characterized circadian clock-HIF interaction in skeletal muscle tissue, and to characterize the role of this interaction in muscle exercise physiology and diet- induced obesity-associated insulin resistance. The overarching goal of this proposal is to understand the molecular mechanisms underlying circadian timing of metabolism and to advance our knowledge of metabolic disease.