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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.
This article was published in the following journal.
Name: Cell reports
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A serine/threonine-protein kinase that functions in AUTOPHAGY in response to starvation. It acts on the PHOSPHATIDYLINOSITOL 3-KINASE complex PIK3C3 to regulate AUTOPHAGOSOME formation. It also functions as both a downstream effector and negative regulator of mammalian target of rapamycin complex 1 (mTORC1) and is activated by AMPK, which it also negatively regulates.
A large group of aerobic bacteria which show up as pink (negative) when treated by the gram-staining method. This is because the cell walls of gram-negative bacteria are low in peptidoglycan and thus have low affinity for violet stain and high affinity for the pink dye safranine.
A group of gram-negative bacteria consisting of rod- and coccus-shaped cells. They are both aerobic (able to grow under an air atmosphere) and microaerophilic (grow better in low concentrations of oxygen) under nitrogen-fixing conditions but, when supplied with a source of fixed nitrogen, they grow as aerobes.
A genus of gram-negative, aerobic or microaerophilic, colorless filaments. It is nonfruiting, motile by gliding, and found in freshwater sediments and cow dung. One species (V. stercoraria) is considered morphologically to be a streptobacillus. That species is strictly aerobic and produces a homodimeric bacterial hemoglobin, especially under oxygen-limited growth conditions. (From Bergey's Manual of Determinative Bacteriology, 9th ed)
A transcriptional regulator in prokaryotes which, when activated by binding cyclic AMP, acts at several promoters. Cyclic AMP receptor protein was originally identified as a catabolite gene activator protein. It was subsequently shown to regulate several functions unrelated to catabolism, and to be both a negative and a positive regulator of transcription. Cell surface cyclic AMP receptors are not included (CYCLIC AMP RECEPTORS), nor are the eukaryotic cytoplasmic cyclic AMP receptor proteins, which are the regulatory subunits of CYCLIC AMP-DEPENDENT PROTEIN KINASES.
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