Jordan Sabine D, Kriebs Anna, Vaughan Megan, Duglan Drew, Fan Weiwei, Henriksson Emma, Huber Anne-Laure, Papp Stephanie J, Nguyen Madelena, Afetian Megan, Downes Michael, Yu Ruth T, Kralli Anastasia, Evans Ronald M, Lamia Katja A
Department of Molecular Medicine, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, CA 92037, USA; Department of Molecular and Cell Biology, University of California, Berkeley, Berkeley, CA 94720, USA.
Department of Molecular Medicine, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, CA 92037, USA.
Cell Metab. 2017 Jul 5;26(1):243-255.e6. doi: 10.1016/j.cmet.2017.06.002.
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 (PPARδ) 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 PPARδ. Cry1;Cry2 myotubes and muscles exhibit elevated expression of PPARδ target genes, particularly in the context of exercise. Notably, CRY1/2 seem to repress a distinct subset of PPARδ 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 PPARδ, and thereby alter energy storage and substrate selection for energy production.
细胞代谢物平衡和线粒体功能受昼夜节律控制，但连接分子时钟与这些功能的途径尚不清楚。过氧化物酶体增殖物激活受体δ（PPARδ）能在运动期间使机体优先利用脂质作为燃料，并且是运动耐力的主要驱动因素。我们在此表明，昼夜节律抑制因子CRY1和CRY2作为PPARδ的共抑制因子发挥作用。Cry1;Cry2肌管和肌肉中PPARδ靶基因的表达升高，尤其是在运动的情况下。值得注意的是，与共抑制因子NCOR1相比，CRY1/2似乎在肌肉中抑制PPARδ靶基因的一个不同子集。在体内，Cry1和Cry2的基因破坏增强了小鼠的短跑运动表现。总体而言，我们的数据表明，CRY1和CRY2通过改变包括CLOCK/BMAL1和PPARδ在内的几种转录因子的活性来调节运动生理学，从而改变能量储存和能量产生的底物选择。
