@article{8ca9a383718847d9be131b482b8fdb09,
title = "CRY1/2 Selectively Repress PPARδ and Limit Exercise Capacity",
abstract = "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. Jordan et al. show that the circadian transcriptional repressors CRY1 and CRY2 repress the nuclear hormone receptor PPARδ and its target genes in mouse skeletal muscle and modulate exercise performance by altering substrate selectivity for energy production.",
keywords = "CRY1, CRY2, PPAR, beta oxidation, circadian, clock, cryptochrome, exercise, muscle, sprint",
author = "Jordan, {Sabine D.} and Anna Kriebs and Megan Vaughan and Drew Duglan and Weiwei Fan and Emma Henriksson and Huber, {Anne Laure} and Papp, {Stephanie J.} and Madelena Nguyen and Megan Afetian and Michael Downes and Yu, {Ruth T.} and Anastasia Kralli and Evans, {Ronald M.} and Lamia, {Katja A.}",
note = "Funding Information: This work was funded by NIH grants K01 DK090188 and R01 DK097164 (to K.A.L.); R37 DK057978 , R01 HL105278 , and CCSG P30 CA014195 (to R.M.E.); R01 DK105126 (to A. Kralli); 1S10OD16357 , which funded the Seahorse Instrument at The Scripps Research Institute; P30 AR061303 , San Diego Muscle Research Center (SDMRC); R24 HD050837 , National Skeletal Muscle Resource Center (NSMRC); a Searle Scholars award to K.A.L. from the Kinship Foundation , the Helmsley Charitable Trust to R.M.E.; and fellowships from Deutsche Forschungsgemeinschaft to S.D.J., the American Heart Association ( 15POST22510020 to S.D.J. and 16PRE3041001 to S.J.P.), and the Swedish Research Council to E.H. R.M.E is an investigator of the Howard Hughes Medical Institute and March of Dimes Chair in Molecular and Developmental Biology at the Salk Institute. We thank the Cancer Research Laboratory Molecular Imaging Center at UC Berkeley and the Biology Faculty Research Fund for use of a Slide Scanner. We thank Enrique Saez, Simon Schenk, Richard Lieber, Velia Fowler, Jamie Williamson, Shannon Bremmner, Carsten Merkwirth, and Andrew Dillin for helpful discussions; sharing of technical expertise, equipment, and reagents; and/or critical reading of the manuscript, and J. Valecko for administrative assistance. Publisher Copyright: {\textcopyright} 2017 Elsevier Inc.",
year = "2017",
month = jul,
day = "5",
doi = "10.1016/j.cmet.2017.06.002",
language = "English (US)",
volume = "26",
pages = "243--255.e6",
journal = "Cell Metabolism",
issn = "1550-4131",
publisher = "Cell Press",
number = "1",
}