Loss of a Negative Regulator of mTORC1 Induces Aerobic Glycolysis and Altered Fiber Composition in Skeletal Muscle

Paul A. Dutchak, Sandi J. Estill-Terpack, Abigail A. Plec, Xiaozheng Zhao, Chendong Yang, Jun Chen, Bookyung Ko, Ralph J. Deberardinis, Yonghao Yu, Benjamin P. Tu

Research output: Contribution to journalArticle

10 Scopus citations

Abstract

The conserved GATOR1 complex consisting of NPRL2-NPRL3-DEPDC5 inhibits mammalian target of rapamycin complex 1 (mTORC1) in response to amino acid insufficiency. Here, we show that loss of NPRL2 and GATOR1 function in skeletal muscle causes constitutive activation of mTORC1 signaling in the fed and fasted states. Muscle fibers of NPRL2 knockout animals are significantly larger and show altered fiber-type composition, with more fast-twitch glycolytic and fewer slow-twitch oxidative fibers. NPRL2 muscle knockout mice also have altered running behavior and enhanced glucose tolerance. Furthermore, loss of NPRL2 induces aerobic glycolysis and suppresses glucose entry into the TCA cycle. Such chronic activation of mTORC1 leads to compensatory increases in anaplerotic pathways to replenish TCA intermediates that are consumed for biosynthetic purposes. These phenotypes reveal a fundamental role for the GATOR1 complex in the homeostatic regulation of mitochondrial functions (biosynthesis versus ATP) to mediate carbohydrate utilization in muscle. Dutchak et al. investigate how mTORC1 activation rewires cellular metabolism in skeletal muscle by analyzing the consequences of loss of NPRL2, a component of the GATOR1 complex that is a conserved negative regulator of mTORC1.

Original languageEnglish (US)
Pages (from-to)1907-1914
Number of pages8
JournalCell Reports
Volume23
Issue number7
DOIs
StatePublished - May 15 2018

Keywords

  • aerobic glycolysis
  • metabolism
  • mitochondria
  • mTORC1
  • muscle physiology
  • Warburg effect

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

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