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Molecular brakes regulating mTORC1 activation in skeletal muscle following synergist ablation

Hamilton, D. Lee, Philp, Andrew, MacKenzie, Matthew G., Patton, Amy, Towler, Mhairi C., Gallagher, Iain J., Bodine, Sue C. and Baar, Keith 2014, Molecular brakes regulating mTORC1 activation in skeletal muscle following synergist ablation, American journal of physiology - endocrinology and metabolism, vol. 307, no. 4, pp. E365-E373, doi: 10.1152/ajpendo.00674.2013.

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Title Molecular brakes regulating mTORC1 activation in skeletal muscle following synergist ablation
Author(s) Hamilton, D. Lee
Philp, Andrew
MacKenzie, Matthew G.
Patton, Amy
Towler, Mhairi C.
Gallagher, Iain J.
Bodine, Sue C.
Baar, Keith
Journal name American journal of physiology - endocrinology and metabolism
Volume number 307
Issue number 4
Start page E365
End page E373
Total pages 9
Publisher American Physiological Society
Place of publication Bethesda, Md.
Publication date 2014-08-15
ISSN 0193-1849
1522-1555
Keyword(s) AMPK
S6K1
hypertrophy
mTORC1
skeletal muscle
AMP-Activated Protein Kinases
Ablation Techniques
Animals
Female
GRB10 Adaptor Protein
Intercellular Signaling Peptides and Proteins
Mechanistic Target of Rapamycin Complex 1
Multiprotein Complexes
Muscle Development
Muscle, Skeletal
Phosphorylation
Rats
Rats, Wistar
Ribosomal Protein S6 Kinases
Signal Transduction
TOR Serine-Threonine Kinases
Weight-Bearing
Science & Technology
Life Sciences & Biomedicine
Endocrinology & Metabolism
Physiology
UNFOLDED PROTEIN RESPONSE
PHOSPHOINOSITIDE 3-KINASE
ENDOPLASMIC-RETICULUM
PHOSPHATIDIC-ACID
INDUCED INCREASE
AMPK ACTIVATION
CELL-GROWTH
CONTRACTIONS
EXPRESSION
Summary 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/IRE1α, 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 Ser(501/503) and S6K1 Thr(389) phosphorylation, two mTORC1 targets that can destabilize IRS proteins. PKB Ser(473) phosphorylation was higher from 3-6 days, and this was associated with increased TSC2 Thr(939) phosphorylation. The phosphorylation of TSC2 (Thr1345) (an AMPK site) was also elevated, whereas phosphorylation at the other PKB site, Thr(1462), was unchanged at 6 days. In agreement with the phosphorylation of Thr(1345), SA led to activation of AMPKα1 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 IRE1α levels decreased. These data suggest that during supraphysiological muscle loading at least three potential molecular brakes engage to downregulate mTORC1.
Language eng
DOI 10.1152/ajpendo.00674.2013
Field of Research 06 Biological Sciences
11 Medical And Health Sciences
HERDC Research category C1.1 Refereed article in a scholarly journal
Copyright notice ©2014, the American Physiological Society
Free to Read? Yes
Use Rights Creative Commons Attribution licence
Persistent URL http://hdl.handle.net/10536/DRO/DU:30112670

Document type: Journal Article
Collections: School of Exercise and Nutrition Sciences
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Every reasonable effort has been made to ensure that permission has been obtained for items included in DRO. If you believe that your rights have been infringed by this repository, please contact drosupport@deakin.edu.au.