hamilton-molecularbrakes-2014.pdf (1.55 MB)
Molecular brakes regulating mTORC1 activation in skeletal muscle following synergist ablation
journal contribution
posted on 2014-08-15, 00:00 authored by Lee HamiltonLee Hamilton, Andrew Philp, Matthew G MacKenzie, Amy Patton, Mhairi C Towler, Iain J Gallagher, Sue C Bodine, Keith BaarThe 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.
History
Journal
American journal of physiology - endocrinology and metabolismVolume
307Issue
4Pagination
E365 - E373Publisher
American Physiological SocietyLocation
Bethesda, Md.Publisher DOI
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ISSN
0193-1849eISSN
1522-1555Language
engPublication classification
C1.1 Refereed article in a scholarly journalCopyright notice
2014, the American Physiological SocietyUsage metrics
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AMPKS6K1hypertrophymTORC1skeletal muscleAMP-Activated Protein KinasesAblation TechniquesAnimalsFemaleGRB10 Adaptor ProteinIntercellular Signaling Peptides and ProteinsMechanistic Target of Rapamycin Complex 1Multiprotein ComplexesMuscle DevelopmentMuscle, SkeletalPhosphorylationRatsRats, WistarRibosomal Protein S6 KinasesSignal TransductionTOR Serine-Threonine KinasesWeight-BearingScience & TechnologyLife Sciences & BiomedicineEndocrinology & MetabolismPhysiologyPHOSPHOINOSITIDE 3-KINASEPHOSPHATIDIC-ACIDINDUCED INCREASEGROWTHEXPRESSIONEXERCISEVARIANTSOVERLOAD
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