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 (PPARδ), a major driver of oxidative metabolism and exercise endurance. CRY-deficient mice exhibit enhanced PPARδ 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 HIF1α-BMAL1 heterodimers. Furthermore, CRY2 appeared to be more effective than CRY1 in the reduction of HIF1α protein steady-state levels in primary myotubes and quadriceps in vivo. Finally, CRY-deficient myotubes exhibit metabolic alterations consistent with cryptochrome-dependent suppression of HIF1α, which likely contributes to circadian modulation of muscle metabolism.

肌肉根据身体活动的强度优先利用糖酵解或氧化代谢。碳水化合物和脂质代谢所需的转录物会在肌肉中发生昼夜节律的表达振荡，并且运动能力和对运动的代谢反应都会受到一天中的时间的影响。昼夜节律抑制剂CRY1和CRY2抑制过氧化物酶体增殖物激活的受体δ（PPARδ），PPARδ是氧化代谢和运动耐力的主要驱动力。CRY缺陷型小鼠在跑步机上跑步时，PPARδ激活增强，最大速度提高，但运动耐力却没有增加。在这里，我们证明了CRYs通过抑制HIF1α-BMAL1异二聚体来限制缺氧反应性转录。此外，体内。最后，CRY缺陷型肌管表现出与隐伏性依赖的HIF1α抑制相一致的代谢改变，这可能有助于肌肉代谢的昼夜节律调节。