Cryptochromes Suppress HIF1α in Muscles

Muscles preferentially utilize glycolytic or oxidative metabolism depending on the intensity of physical activity. Transcripts required for carbohydrate and lipid metabolism undergo circadian oscillations of expression in muscles, and both exercise capacity and the metabolic response to exercise are influenced by time of day. The circadian repressors CRY1 and CRY2 repress peroxisome proliferator-activated receptor delta (PPAR delta), a major driver of oxidative metabolism and exercise endurance. CRY-deficient mice exhibit enhanced PPARd activation and greater maximum speed when running on a treadmill but no increase in exercise endurance. Here we demonstrate that CRYs limit hypoxia-responsive transcription via repression of HIF1 alpha-BMAL1 heterodimers. Furthermore, CRY2 appeared to be more effective than CRY1 in the reduction of HIF1 alpha protein steady-state levels in primary myotubes and quadriceps in vivo. Finally, CRY-deficient myotubes exhibit metabolic alterations consistent with cryptochrome-dependent suppression of HIF1 alpha, which likely contributes to circadian modulation of muscle metabolism.