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

Cell Rep. 2018 May 15;23(7):1907-1914. doi: 10.1016/j.celrep.2018.04.058.


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.

Keywords: Warburg effect; aerobic glycolysis; mTORC1; metabolism; mitochondria; muscle physiology.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Aerobiosis
  • Amino Acids / metabolism
  • Animals
  • Behavior, Animal
  • Carbohydrate Metabolism
  • Citric Acid Cycle
  • Glycolysis*
  • Mechanistic Target of Rapamycin Complex 1 / metabolism*
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Muscle Fibers, Skeletal / metabolism*
  • Tumor Suppressor Proteins / metabolism


  • Amino Acids
  • Tumor Suppressor Proteins
  • Mechanistic Target of Rapamycin Complex 1