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

Cell Reports
Paul A DutchakBenjamin P Tu

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.

Citations

Aug 14, 2018·Current Opinion in Supportive and Palliative Care·Ryan N MontalvoJames A Carson
Dec 1, 2018·Journal of Cachexia, Sarcopenia and Muscle·Francesca RiuzziRosario Donato
Mar 31, 2019·Journal of Cachexia, Sarcopenia and Muscle·Olivier Le BacquerStéphane Walrand
Dec 11, 2019·Cells·Cedric MagawayEstela Jacinto
Oct 17, 2018·Frontiers in Cell and Developmental Biology·Isabelle Bourdeau JulienPaul A Dutchak
Oct 3, 2020·Molecular Cancer·Tianshui SunQing Yang
Sep 19, 2020·Experimental & Molecular Medicine·Hee Chan YooJung Min Han
Oct 13, 2020·Advanced Science·Xiaopeng ZhuXingxing Kong
Oct 22, 2020·The Journal of Biological Chemistry·Myriam SévignyChantelle F Sephton
Feb 19, 2021·Physiological Reviews·Angelia SzwedEstela Jacinto
Jan 18, 2021·The Journal of Biological Chemistry·Myriam SévignyChantelle F Sephton
Jul 3, 2021·Cancers·Ryan W Holloway, Paola A Marignani
Dec 30, 2021·Human Molecular Genetics·Saeko IshidaKohichi Tanaka

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