Please use this identifier to cite or link to this item: http://hdl.handle.net/1893/22554
Appears in Collections:Faculty of Health Sciences and Sport Journal Articles
Peer Review Status: Refereed
Title: Molecular brakes regulating mTORC1 activation in skeletal muscle following synergist ablation
Authors: Hamilton, David Lee
Philp, Andrew
MacKenzie, Matthew G
Patton, Amy
Towler, Mhairi C
Gallagher, Iain J
Bodine, Sue C
Baar, Keith
Contact Email: i.j.gallagher@stir.ac.uk
Keywords: mTORC1
S6K1
AMPK
hypertrophy
skeletal muscle
Issue Date: 15-Aug-2014
Publisher: American Physiological Society
Citation: Hamilton DL, Philp A, MacKenzie MG, Patton A, Towler MC, Gallagher IJ, Bodine SC & Baar K (2014) Molecular brakes regulating mTORC1 activation in skeletal muscle following synergist ablation, American Journal of Physiology - Endocrinology and Metabolism, 307 (4), pp. E365-E373.
Abstract: The goal of the current work was to profile positive (mTORC1 activation, autocrine/paracrine growth factors) and negative [AMPK, unfolded protein response (UPR)] pathways that might regulate overload-induced mTORC1 (mTOR complex 1) activation with the hypothesis that a number of negative regulators of mTORC1 will be engaged during a supraphysiological model of hypertrophy. To achieve this, mTORC1- IRS-1/2 signaling, BiP/CHOP/IRE1, and AMPK activation were determined in rat plantaris muscle following synergist ablation (SA). SA resulted in significant increases in muscle mass of 4% per day throughout the 21 days of the experiment. The expression of the insulin-like growth factors (IGF) were high throughout the 21st day of overload. However, IGF signaling was limited, since IRS-1 and -2 were undetectable in the overloaded muscle from day 3 to day 9. The decreases in IRS-1/2 protein were paralleled by increases in GRB10 Ser501/503 and S6K1 Thr389 phosphorylation, two mTORC1 targets that can destabilize IRS proteins. PKB Ser473 phosphorylation was higher from 3– 6 days, and this was associated with increased TSC2 Thr939 phosphorylation. The phosphorylation of TSC2 Thr1345 (an AMPK site) was also elevated, whereas phosphorylation at the other PKB site, Thr1462, was unchanged at 6 days. In agreement with the phosphorylation of Thr1345, SA led to activation of AMPK1 during the initial growth phase, lasting the first 9 days before returning to baseline by day 12. The UPR markers CHOP and BiP were elevated over the first 12 days following ablation, whereas IRE1 levels decreased. These data suggest that during supraphysiological muscle loading at least three potential molecular brakes engage to downregulate mTORC1. mT
Type: Journal Article
URI: http://hdl.handle.net/1893/22554
DOI Link: http://dx.doi.org/10.1152/ajpendo.00674.2013
Rights: Licensed under Creative Commons CC-BY 3.0: the American Physiological Society. Open access publishing allows free access to and distribution of published articles where the author retains copyright of their work by employing a Creative Commons attribution licence. Proper attribution of authorship and correct citation details should be given.
Affiliation: Sport
University of Birmingham
University of Dundee
University of California, Davis
University of Dundee
Sport
University of California, Davis
University of California, Davis

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