•CRY1 and CRY2 interact with PPARδ in a ligand-dependent manner•CRY1/2 repress PPARδ target gene expression in myotubes•Genetic ablation of CRY1 and CRY2 increases exercise capacity in mice•Exercise-induced muscle gene signature is altered in CRY−/− miceCellular metabolite balance and mitochondrial function are under circadian control, but the pathways connecting the molecular clock to these functions are unclear. Peroxisome proliferator-activated receptor delta (PPARδ) enables preferential utilization of lipids as fuel during exercise and is a major driver of exercise endurance. We show here that the circadian repressors CRY1 and CRY2 function as co-repressors for PPARδ. Cry1−/−;Cry2−/− myotubes and muscles exhibit elevated expression of PPARδ target genes, particularly in the context of exercise. Notably, CRY1/2 seem to repress a distinct subset of PPARδ target genes in muscle compared to the co-repressor NCOR1. In vivo, genetic disruption of Cry1 and Cry2 enhances sprint exercise performance in mice. Collectively, our data demonstrate that CRY1 and CRY2 modulate exercise physiology by altering the activity of several transcription factors, including CLOCK/BMAL1 and PPARδ, and thereby alter energy storage and substrate selection for energy production.Download high-res image (228KB)Download full-size image

Circadian clocks coordinate behavior and physiology with daily environmental cycles and thereby optimize the timing of metabolic processes such as glucose production and insulin secretion. Such circadian regulation of metabolism provides an adaptive advantage in diverse organisms. Mammalian clocks are primarily based on a transcription and translation feedback loop in which a heterodimeric complex of the transcription factors CLOCK (circadian locomotor output cycles kaput) and BMAL1 (brain and muscle Arnt-like protein 1) activates the expression of its own repressors, the period (PER1–3) and cryptochrome (CRY1 and CRY2) proteins. Posttranslational modification of these core clock components is critical for setting clock time or adjusting the speed of the clock. AMP-activated protein kinase (AMPK) is one of several metabolic sensors that have been reported to transmit energy-dependent signals to the mammalian clock. AMPK does so by driving the phosphorylation and destabilization of CRY and PER proteins. In addition, AMPK subunit composition, sub-cellular localization, and substrate phosphorylation are dependent on clock time. Given the well-established role of AMPK in diverse aspects of metabolic physiology, the reciprocal regulation of AMPK and circadian clocks likely plays an important role in circadian metabolic regulation.Highlights► Circadian clocks regulate mammalian metabolic physiology. ► AMPK contributes to clock time setting by phosphorylating clock component proteins. ► AMPK activity, subunit composition, and localization depend on clock time.