Cryptochromes Suppress HIF1α in Muscles.
Cryptochromes Suppress HIF1α in Muscles.
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隐花色素抑制肌肉中的 HIF1α。
DOI：
10.1016/j.isci.2020.101338
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发表时间：
2020
期刊：
影响因子：
5.8
通讯作者：
Lamia,KatjaA
中科院分区：
文献类型：
--
作者：
Vaughan,MeganE;Wallace,Martina;Handzlik,MichalK;Chan,AlannaB;Metallo,ChristianM;Lamia,KatjaA
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本在肌肉中的表达经历昼夜振荡，运动能力和运动代谢反应都受到一天中的时间的影响。昼夜节律抑制因子CRY1和CRY2抑制过氧化物酶体增殖物激活受体δ (PPARδ)，这是氧化代谢和运动耐力的主要驱动因素。哭泣缺陷小鼠在跑步机上跑步时表现出增强的PPARδ激活和更高的最大速度，但运动耐力没有增加。在这里，我们证明CRYs通过抑制HIF1α-BMAL1异源二聚体来限制缺氧反应转录。此外，CRY2似乎比CRY1更有效地降低原代肌管和股四头肌的体内HIF1α蛋白稳态水平。最后，cry缺陷肌管表现出与隐色素依赖性HIF1α抑制一致的代谢改变，这可能有助于肌肉代谢的昼夜节律调节。
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 quadricepsin vivo. Finally, CRY-deficient myotubes exhibit metabolic alterations consistent with cryptochrome-dependent suppression of HIF1α, which likely contributes to circadian modulation of muscle metabolism.