Mus musculus Transcriptome or Gene expression

Circadian clocks have emerged as major regulators of mammalian metabolic physiology. We show here that the circadian repressors CRY1 and CRY2 function as co-repressors for the peroxisome proliferator activated receptor delta (PPARd) and thereby modulate mitochondrial substrate utilization. PPARd enables preferential utilization of lipids as fuel during exercise and is a major driver of exercise endurance. Genetic disruption of Cry1 and Cry2 results in enhanced mitochondrial respiratory capacity in myotubes and increased exercise capacity in vivo in the absence of major alterations in muscle fiber type composition or mitochondrial content. Cry1-/-;Cry2-/- cells and muscles exhibit elevated expression of PPARd target genes, particularly in the context of exercise. Notably, CRY1/2 seem to repress a distinct subset of PPARd target genes and functions in muscle compared to those regulated by the co-repressor NCOR1. Collectively, our data demonstrate that CRY1 and CRY2 link the molecular circadian clock to PPARd-driven influences on mitochondrial function and exercise physiology.