title: Creb coactivators direct anabolic responses and enhance performance of skeletal muscle.
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.
authors.affiliation: Department of Cancer Biology, The Scripps Research Institute Scripps Florida, Jupiter, FL, USA.
authors.forename: Nelson E
authors.initials: NE
authors.lastname: Bruno
authors.forename: Kimberly A
authors.initials: KA
authors.lastname: Kelly
authors.forename: Richard
authors.initials: R
authors.lastname: Hawkins
authors.forename: Mariam
authors.initials: M
authors.lastname: Bramah-Lawani
authors.forename: Antonio L
authors.initials: AL
authors.lastname: Amelio
authors.forename: Jerome C
authors.initials: JC
authors.lastname: Nwachukwu
authors.forename: Kendall W
authors.initials: KW
authors.lastname: Nettles
authors.forename: Michael D
authors.initials: MD
authors.lastname: Conkright
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D002395:Catecholamines / Q000378:metabolism / Q000494:pharmacology; D002478:Cells, Cultured; D017079:Exercise Tolerance / Q000187:drug effects / Q000235:genetics*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D018482:Muscle, Skeletal / Q000378:metabolism*; D010805:Physical Conditioning, Animal / Q000502:physiology; D013564:Sympathetic Nervous System / Q000378:metabolism*; D014157:Transcription Factors / Q000502:physiology*
chemical_list: C555318:CRTC3 protein, mouse; D002395:Catecholamines; C504923:Crtc2 protein, mouse; D014157:Transcription Factors