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CRY1/2 Selectively Repress PPARδ and Limit Exercise Capacity

Jordan, Sabine D. ; Kriebs, Anna ; Vaughan, Megan ; Duglan, Drew ; Fan, Weiwei ; Henriksson, Emma ; Huber, Anne Laure ; Papp, Stephanie J. ; Nguyen, Madelena and Afetian, Megan , et al. (2017) In Cell Metabolism 26(1). p.6-255
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... (More)

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.

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organization
publishing date
type
Contribution to journal
publication status
published
subject
keywords
beta oxidation, circadian, clock, CRY1, CRY2, cryptochrome, exercise, muscle, PPAR, sprint
in
Cell Metabolism
volume
26
issue
1
pages
6 - 255
publisher
Cell Press
external identifiers
  • scopus:85027411247
  • pmid:28683290
ISSN
1550-4131
DOI
10.1016/j.cmet.2017.06.002
language
English
LU publication?
no
id
17024bda-6954-4b5f-9338-f9117aecc106
date added to LUP
2018-01-25 12:35:55
date last changed
2024-03-31 22:36:44
@article{17024bda-6954-4b5f-9338-f9117aecc106,
  abstract     = {{<p>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<sup>−/−</sup>;Cry2<sup>−/−</sup> 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.</p>}},
  author       = {{Jordan, Sabine D. and Kriebs, Anna and Vaughan, Megan and Duglan, Drew and Fan, Weiwei and Henriksson, Emma and Huber, Anne Laure and Papp, Stephanie J. and Nguyen, Madelena and Afetian, Megan and Downes, Michael and Yu, Ruth T. and Kralli, Anastasia and Evans, Ronald M. and Lamia, Katja A.}},
  issn         = {{1550-4131}},
  keywords     = {{beta oxidation; circadian; clock; CRY1; CRY2; cryptochrome; exercise; muscle; PPAR; sprint}},
  language     = {{eng}},
  month        = {{07}},
  number       = {{1}},
  pages        = {{6--255}},
  publisher    = {{Cell Press}},
  series       = {{Cell Metabolism}},
  title        = {{CRY1/2 Selectively Repress PPARδ and Limit Exercise Capacity}},
  url          = {{http://dx.doi.org/10.1016/j.cmet.2017.06.002}},
  doi          = {{10.1016/j.cmet.2017.06.002}},
  volume       = {{26}},
  year         = {{2017}},
}