CRY1/2 Selectively Repress PPARδ and Limit Exercise Capacity

Cellular 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 (PPAR delta) 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 PPAR delta. Cry1(-/-); Cry2(-/-) myotubes and muscles exhibit elevated expression of PPAR delta target genes, particularly in the context of exercise. Notably, CRY1/2 seem to repress a distinct subset of PPAR delta 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 PPAR delta, and thereby alter energy storage and substrate selection for energy production.