Despite recent advances in uncovering the role of circadian clocks in cardiometabolic disease, 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. In my recently published K01-funded studies, I have discovered reciprocal interactions between the skeletal muscle circadian clock and the nutrient-sensitive hypoxia-inducible factor (HIF) transcription pathway. Specifically, I found that (i) that circadian transcription factors regulate hypoxic HIF1? activation and anaerobic glycolysis in muscle myotubes, (ii) hypoxia/HIF reciprocally regulates clock transcriptional activity and period length in myotubes, and (iii) the circadian clock establishes time-of-day dependent response to exercise-induced HIF activation in skeletal muscle. Collectively, our data reveal coupling of the hypoxia-inducible factor and circadian pathway producing rhythmic adaptation to hypoxic stress. However, it is still unclear how this coupling occurs and whether in vivo circadian disruption would impair HIF-dependent functions, such as muscle glucose uptake and acute strenuous exercise tolerance. My present proposed studies are to utilize an array of innovative models and techniques to build upon my 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.
The escalation of metabolic disease, including obesity and type 2 diabetes mellitus, has emerged as a worldwide public health challenge, and increasing evidence indicates that susceptibility to these disorders are 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 glucose homeostasis. 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.
