HIF1α Mediates Circadian Regulation of Skeletal Muscle Metabolism and Substrate Preference in Response to Time-of-Day Exercise

The regulation of metabolism in peripheral tissues is mediated by pathways that are under circadian control. a bidirectional relationship is evident between the circadian clock and hypoxia-inducible factor-1 α (HIF1α), which is specific to time-of-day exercise. To elucidate the role of HIF1α in driving the divergences in the systemic and skeletal muscle metabolic responses to exercise, a skeletal muscle-specific HIF1α knockout (KO) mouse model was generated. Metabolic phenotyping alongside global transcriptomic profiling was conducted under basal conditions or in response to an acute exercise bout in HIF1α KO and wild-type (WT) mice at the early rest phase (ZT3) or early active phase (ZT15). Our findings demonstrate that HIF1α is dispensable for the metabolic response to exercise at ZT15, but required for an elevation in glycolytic metabolism in response to exercise at ZT3. Specifically, the loss of HIF1α alters the fate of glucose with a shift towards mannose-6-phosphate production observed at ZT3. In addition, the loss of HIF1α alters the transcriptional profile of skeletal muscle specifically at ZT3 with a shift towards oxidative metabolism. HIF1α contributes to regulating the time-of-day exercise response by driving a shift in substrate preference primarily towards glucose oxidation while sparing fatty acid oxidation. This comprehensive metabolic phenotyping of HIF1α KO mice demonstrates that the contribution of HIF1α to the regulation of time-of-day metabolism is dependent on metabolic status and energetic stressors.