Role of Clock-HIF signaling in adult muscle stem cell regenerative capacity during obesity

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 and developmental stage-specific manner. Our previously published studies uncovered novel reciprocal interactions between the skeletal muscle circadian clock and the nutrient-sensitive hypoxia-inducible factor (HIF) transcription pathway. Specifically, we demonstrated coupling of the hypoxia-inducible factor and circadian pathways producing rhythmic adaptation to hypoxic stress. However, it is still unclear how this coupling acts to regulate transcription and metabolic fuel selection, and whether in vivo circadian disruption would impair HIF-dependent functions, such as muscle regeneration following injury. Due to the known effects of high fat diet on both impaired muscle injury repair and circadian clock dysfunction, we propose here to test the hypothesis that high-fat diet impairs muscle stem cell repair thereby reducing muscle glucose oxidative capacity through disruption of the circadian clock. Overall, we believe these studies will provide genetic models to test 1) role of the clock-HIF pathway in muscle stem cell proliferation and differentiation 2) circadian realignment by restricted feeding as a means of maintaining healthy muscle tissue regeneration in conditions such as obesity and type 2 diabetes.