Mammalian target of rapamycin complex 2 regulates muscle glucose uptake during exercise in mice

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Exercise increases glucose uptake into insulin-resistant muscle. Thus, elucidating the exercise signalling network in muscle may uncover new therapeutic targets. mTORC2, a regulator of insulin-controlled glucose uptake, has been reported to interact with Rac1, which plays a role in exercise-induced glucose uptake in muscle. Therefore, we tested the hypothesis that mTORC2 activity is necessary for muscle glucose uptake during treadmill exercise. We used mice that specifically lack mTORC2 signalling in muscle, by deletion of the obligatory mTORC2 component, Rictor (Ric mKO). Running capacity and running-induced changes in blood glucose, plasma lactate and muscle glycogen levels were similar in Ric WT and Ric mKO mice. At rest, muscle glucose uptake was normal, but during running muscle glucose uptake was reduced by 40% in Ric mKO mice. Running increased muscle p-AMPK similarly in Ric WT and Ric mKO mice and GLUT4 and HKII protein expressions were also normal in Ric mKO muscle. The mTORC2 substrate, p-PKCα, and the mTORC2 activity readout, p-NDRG1, increased with running in Ric WT mice, but were not altered by running in Ric mKO muscle. Quantitative phosphoproteomics uncovered several additional potential exercise-dependent mTORC2 substrates, including contractile proteins, kinases, transcriptional regulators, actin cytoskeleton regulators and ion-transport proteins. Our study suggests that mTORC2 is a component of the exercise signalling network that regulates muscle glucose uptake and we provide a resource of new potential members of the mTORC2 signalling network. This article is protected by copyright. All rights reserved.

Original languageEnglish
JournalJournal of Physiology
Issue number14
Pages (from-to)4845-4855
Number of pages11
Publication statusPublished - 2017

    Research areas

  • mTOR, Running, NDRG, Phosphoproteomics

ID: 178257401