HIF1a 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 a (HIF1a), which is specific to time-of-day exercise. To elucidate the role of HIF1a in driving the divergences in the systemic and skeletal muscle metabolic responses to exercise, a skeletal muscle-specific HIF1a 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 HIF1a KO and wild-type (WT) mice at the early rest phase (ZT3) or early active phase (ZT15). Our findings demonstrate that HIF1a 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 HIF1a alters the fate of glucose with a shift towards mannose-6-phosphate production observed at ZT3. In addition, the loss of HIF1a alters the transcriptional profile of skeletal muscle specifically at ZT3 with a shift towards oxidative metabolism. HIF1a 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 HIF1a KO mice demonstrates that the contribution of HIF1a to the regulation of time-of-day metabolism is dependent on metabolic status and energetic stressors. Overall design: To determine the role of skeletal muscle HIF1a in mediating the transcriptional responses to time-of-day, a skeletal muscle-specific HIF1a knockout mouse was generated (HIF1a KO). Skeletal muscle specific HIF1a knock out and wild type mice were subjected to 60 min treadmill running (16 m/min, 5 % incline) or a sham treatment at zeitgeber time (ZT) 3 and ZT 15. RNA sequencing was performed on gastrocnemius tissue of mice 3 hr following the treatment. The sample 'ko_3_ex_44' (GSM8647977), also referred to as '0156_44' in the GSE282641_rawCounts.txt.gz file, was excluded from downstream analysis due to low coverage.