CRY1/2 Selectively Repress PPARδ and Limit Exercise Capacity

Sabine D. Jordan, Anna Kriebs, Megan Vaughan, Drew Duglan, Weiwei Fan, Emma Henriksson, Anne Laure Huber, Stephanie J. Papp, Madelena Nguyen, Megan Afetian, Michael Downes, Ruth T. Yu, Anastasia Kralli, Ronald M. Evans, Katja A. Lamia

Research output: Contribution to journalArticlepeer-review

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.

Original languageEnglish (US)
Pages (from-to)243-255.e6
JournalCell Metabolism
Volume26
Issue number1
DOIs
StatePublished - Jul 5 2017

Keywords

  • CRY1
  • CRY2
  • PPAR
  • beta oxidation
  • circadian
  • clock
  • cryptochrome
  • exercise
  • muscle
  • sprint

ASJC Scopus subject areas

  • Physiology
  • Molecular Biology
  • Cell Biology

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