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This Article Full Text Full Text (PDF) All Versions of this Article: JOE-09-0202v1 202/3/441    most recent Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via Web of Science (1) Citing Articles via Google Scholar Google Scholar Articles by Rivas, D. A Articles by Lessard, S. J Search for Related Content PubMed PubMed Citation Articles by Rivas, D. A Articles by Lessard, S. J

Exercise Metabolism Group, School of Medical Sciences, RMIT University, Bundoora, Victoria 3083, Australia
¹ Exercise Biochemistry Lab, Department of Kinesiology, California State University, Northridge, California 91330, USA

(Correspondence should be addressed to S J Lessard who is now at Research Division, Metabolism Section, Joslin Diabetes Center, Level 5, 1 Joslin Place, Boston, Massachusetts 02215, USA; Email: sarah.lessard{at}joslin.harvard.edu)

The serine/threonine protein kinase, mammalian target of rapamycin (mTOR) is regulated by insulin and nutrient availability and has been proposed to play a central role as a nutrient sensor in skeletal muscle. mTOR associates with its binding partners, raptor and rictor, to form two structurally and functionally distinct complexes, mTOR complex 1 (mTORC1) and mTOR complex 2 (mTORC2) respectively. We have investigated the assembly of mTORC1/2 and the activation of their downstream substrates (i.e. Akt, S6K1) in response to known effectors of mTOR, excess lipid availability and AMP-activated protein kinase (AMPK) activation/exercise training in rat skeletal muscle. The in vivo formation of mTORC1 and 2 and the activation of their respective downstream substrates were increased in response to chronic (8 weeks) consumption of a high-fat diet. Diet-induced mTORC activation and skeletal muscle insulin resistance were reversed by 4 weeks of exercise training, which was associated with enhanced muscle AMPK activation. In order to determine whether AMPK activation reverses lipid-induced mTOR activation, L6 myotubes were exposed to 0.4 mM palmitate to activate mTORC1/2 in the absence or presence of 5'-aminoimidazole-4-carboxamide-1-β-D-ribofuranoside (AICAR). Palmitate exposure (4 h) increased insulin-stimulated S6K1 Thr389 phosphorylation by 60%, indicating activation of mTORC1. AMPK activation with 1 mM AICAR abolished lipid-induced mTOR activation in vitro. Our data implicates reductions in mTOR complex activation with the reversal of lipid-induced skeletal muscle insulin resistance in response to exercise training or AICAR and identifies mTOR as a potential target for the treatment of insulin resistance.