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Creb coactivators direct anabolic responses and enhance performance of skeletal muscle

Nelson E Bruno, Kimberly A Kelly, Richard Hawkins, Mariam Bramah‐Lawani, Antonio L Amelio, Jerome C Nwachukwu, Kendall W Nettles, Michael D Conkright

Author Affiliations

  1. Nelson E Bruno1,2,
  2. Kimberly A Kelly1,
  3. Richard Hawkins1,
  4. Mariam Bramah‐Lawani13,
  5. Antonio L Amelio1,
  6. Jerome C Nwachukwu1,
  7. Kendall W Nettles1 and
  8. Michael D Conkright*,1,2
  1. 1Department of Cancer Biology, The Scripps Research Institute Scripps Florida, Jupiter, FL, USA
  2. 2The Center for Diabetes and Metabolic Diseases, The Scripps Research Institute Scripps Florida, Jupiter, FL, USA
  3. 3Present address: Vaccine & Gene Therapy Institute of Florida, Port St. Lucie, FL, USA
  1. *Corresponding author. Tel: +1 561 228 3204; Fax: +1 561 228 3057; E‐mail: Conkright{at}scripps.edu
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Abstract

During the stress response to intense exercise, the sympathetic nervous system (SNS) induces rapid catabolism of energy reserves through the release of catecholamines and subsequent activation of protein kinase A (PKA). Paradoxically, chronic administration of sympathomimetic drugs (β‐agonists) leads to anabolic adaptations in skeletal muscle, suggesting that sympathetic outflow also regulates myofiber remodeling. Here, we show that β‐agonists or catecholamines released during intense exercise induce Creb‐mediated transcriptional programs through activation of its obligate coactivators Crtc2 and Crtc3. In contrast to the catabolic activity normally associated with SNS function, activation of the Crtc/Creb transcriptional complex by conditional overexpression of Crtc2 in the skeletal muscle of transgenic mice fostered an anabolic state of energy and protein balance. Crtc2‐overexpressing mice have increased myofiber cross‐sectional area, greater intramuscular triglycerides and glycogen content. Moreover, maximal exercise capacity was enhanced after induction of Crtc2 expression in transgenic mice. Collectively these findings demonstrate that the SNS‐adrenergic signaling cascade coordinates a transient catabolic stress response during high‐intensity exercise, which is followed by transcriptional reprogramming that directs anabolic changes for recovery and that augments subsequent exercise performance.

Synopsis

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The sympathetic nervous system coordinates catabolism of energy stores during exercise with anabolic responses post‐exercise by activating the Crtc/Creb transcriptional complex.

  • High‐intensity exercise activates the Crtc/Creb transcriptional complex to direct anabolism.

  • Adrenergic and cholinergic signaling converge on Crtc‐mediated transcription.

  • Sustained activation of the Crtc/Creb complex in skeletal muscle increases maximal exercise capacity.

The EMBO Journal (2014) 33: 1027–1043

  • Received July 1, 2013.
  • Revision received February 1, 2014.
  • Accepted February 20, 2014.
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