Loss of a Negative Regulator of mTORC1 Induces Aerobic Glycolysis and Altered Fiber Composition in Skeletal Muscle
Open accessAbstract
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.
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From Glutamine reliance in cell metabolism (2020) · cites this paper as [163]
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Cites
The Biology of Cancer: Metabolic Reprogramming Fuels Cell Growth and Proliferation
DeBerardinis, R. J., Lum, J. J., Hatzivassiliou, G., & Thompson, C. B. (2008) · Cell Metabolism · doi:10.1016/j.cmet.2007.10.002 · Cited by 4,088 · see citing works
Self-citationA Cold-Inducible Coactivator of Nuclear Receptors Linked to Adaptive Thermogenesis
Puigserver, P., Wu, Z., Park, C. W., Graves, R., Wright, M., & Spiegelman, B. M. (1998) · Cell · doi:10.1016/s0092-8674(00)81410-5 · Cited by 3,864 · see citing works
TSC2 is phosphorylated and inhibited by Akt and suppresses mTOR signalling
Inoki, K., Li, Y., Zhu, T., Wu, J., & Guan, K.-L. (2002) · Nature Cell Biology · doi:10.1038/ncb839 · Cited by 3,083 · see citing works
Molecular mechanisms of mTOR-mediated translational control
Ma, X. M., & Blenis, J. (2009) · Nature Reviews Molecular Cell Biology · doi:10.1038/nrm2672 · Cited by 2,558 · see citing works
Skeletal muscle fatigue: cellular mechanisms
Allen, D. G., Lamb, G. D., & Westerblad, H. (2008) · Physiological Reviews · doi:10.1152/physrev.00015.2007 · Cited by 2,495 · see citing works
Sancak, Y., Bar-Peled, L., Zoncu, R., Markhard, A. L., Nada, S., & Sabatini, D. M. (2010) · Cell · doi:10.1016/j.cell.2010.02.024 · Cited by 2,464 · see citing works
Jung, C. H., Ro, S.-H., Cao, J., Otto, N. M., & Kim, D.-H. (2010) · FEBS Letters · doi:10.1016/j.febslet.2010.01.017 · Cited by 2,090 · see citing works
Activation of a metabolic gene regulatory network downstream of mTOR complex 1
Düvel, K., Yecies, J. L., Menon, S., Raman, P., Lipovsky, A. I., Souza, A. L., Triantafellow, E., Ma, Q., Gorski, R., Cleaver, S., et al. (2010) · Molecular Cell · doi:10.1016/j.molcel.2010.06.022 · Cited by 2,020 · see citing works
Regulation of translation initiation by FRAP/mTOR
Gingras, A.-C., Raught, B., & Sonenberg, N. (2001) · Genes & Development · doi:10.1101/gad.887201 · Cited by 1,545 · see citing works
Hudson, C. C., Liu, M., Chiang, G. G., Otterness, D. M., Loomis, D. C., Kaper, F., Giaccia, A. J., & Abraham, R. T. (2002) · Molecular and Cellular Biology · doi:10.1128/mcb.22.20.7004-7014.2002 · Cited by 1,186 · see citing works
Exercise-induced BCL2-regulated autophagy is required for muscle glucose homeostasis
He, C., Bassik, M. C., Moresi, V., Sun, K., Wei, Y., Zou, Z., An, Z., Loh, J., Fisher, J., Sun, Q., et al. (2012) · Nature · doi:10.1038/nature10758 · Cited by 1,136 · see citing works
The TSC1-2 tumor suppressor controls insulin–PI3K signaling via regulation of IRS proteins
Harrington, L. S., Findlay, G. M., Gray, A., Толкачева, Т. А., Wigfield, S., Rebholz, H., Barnett, J., Leslie, N. R., Cheng, S., Shepherd, P. R., et al. (2004) · The Journal of Cell Biology · doi:10.1083/jcb.200403069 · Cited by 1,123 · see citing works
Hsu, P. P., Kang, S. A., Rameseder, J., Zhang, Y., Ottina, K. A., Lim, D., Peterson, T. R., Choi, Y., Gray, N. S., Yaffe, M. B., et al. (2011) · Science · doi:10.1126/science.1199498 · Cited by 1,084 · see citing works
Bar-Peled, L., Chantranupong, L., Cherniack, A. D., Chen, W. W., Ottina, K. A., Grabiner, B. C., Spear, E. D., Carter, S. L., Meyerson, M., & Sabatini, D. M. (2013) · Science · doi:10.1126/science.1232044 · Cited by 1,080 · cited 2× · see citing works
“for small RAG GTPases to inhibit mTORC1 during amino acid limitation (Bar-Peled et al., 2013; Dutchak et al., 2015; Neklesa and Davis, 2009; Panchaud et al., 2013).”
BackgroundMaking new contacts: the mTOR network in metabolism and signalling crosstalk
Shimobayashi, M., & Hall, M. N. (2014) · Nature Reviews Molecular Cell Biology · doi:10.1038/nrm3757 · Cited by 1,053 · see citing works
Skeletal muscle metabolism is a major determinant of resting energy expenditure.
Zurlo, F., Larson, K., Bogardus, C., & Ravussin, E. (1990) · Journal of Clinical Investigation · doi:10.1172/jci114857 · Cited by 959 · see citing works
Yu, Y., Yoon, S.-O., Poulogiannis, G., Yang, Q., Ma, X. M., Villén, J., Kubica, N., Hoffman, G. R., Cantley, L. C., Gygi, S. P., et al. (2011) · Science · doi:10.1126/science.1199484 · Cited by 855 · see citing works
Self-citationTee, A. R., Fingar, D. C., Manning, B. D., Kwiatkowski, D. J., Cantley, L. C., & Blenis, J. (2002) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.202476899 · Cited by 827 · see citing works
Choo, A. Y., Yoon, S.-O., Kim, S. G., Roux, P. P., & Blenis, J. (2008) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0809136105 · Cited by 813 · see citing works
mTORC1 induces purine synthesis through control of the mitochondrial tetrahydrofolate cycle
Ben-Sahra, I., Hoxhaj, G., Ricoult, S. J. H., Asara, J. M., & Manning, B. D. (2016) · Science · doi:10.1126/science.aad0489 · Cited by 795 · see citing works
Stimulation of de novo pyrimidine synthesis by growth signaling through mTOR and S6K1
Ben-Sahra, I., Howell, J. J., Asara, J. M., & Manning, B. D. (2013) · Science · doi:10.1126/science.1228792 · Cited by 739 · see citing works
Bentzinger, C. F., Romanino, K., Cloëtta, D., Lin, S., Mascarenhas, J. B., Oliveri, F., Xia, J., Casanova, E., Costa, C. F., Brink, M., et al. (2008) · Cell Metabolism · doi:10.1016/j.cmet.2008.10.002 · Cited by 640 · see citing works
Quantitative Phosphoproteomics Reveal mTORC1 Activates de Novo Pyrimidine Synthesis
Robitaille, A. M., Christen, S., Shimobayashi, M., Cornu, M., Fava, L. L., Moes, S., Prescianotto-Baschong, C., Sauer, U., Jenoe, P., & Hall, M. N. (2013) · Science · doi:10.1126/science.1228771 · Cited by 525 · see citing works
Skeletal Muscle Fiber Type: Influence on Contractile and Metabolic Properties
Zierath, J. R., & Hawley, J. A. (2004) · PLoS Biology · doi:10.1371/journal.pbio.0020348 · Cited by 518 · see citing works
Regulation of mTORC1 by the Rag GTPases is necessary for neonatal autophagy and survival
Efeyan, A., Zoncu, R., Chang, S. H., Gumper, I., Snitkin, H., Wolfson, R. L., Kirak, O., Sabatini, D. M., & Sabatini, D. M. (2012) · Nature · doi:10.1038/nature11745 · Cited by 457 · see citing works
Skeletal muscle: Energy metabolism, fiber types, fatigue and adaptability
Westerblad, H., Bruton, J. D., & Katz, A. (2010) · Experimental Cell Research · doi:10.1016/j.yexcr.2010.05.019 · Cited by 334 · see citing works
Castets, P., Lin, S., Rion, N., Di Fulvio, S., Romanino, K., Guridi, M., Frank, S., Tintignac, L. A., Sinnreich, M., & Rüegg, M. A. (2013) · Cell Metabolism · doi:10.1016/j.cmet.2013.03.015 · Cited by 302 · see citing works
Panchaud, N., Gulli, M., & VIRGILIO, C. D. (2013) · Science Signaling · doi:10.1126/scisignal.2004112 · Cited by 290 · see citing works
Liu, P., Gan, W., Inuzuka, H., Lazorchak, A. S., Gao, D., Arojo, O., Liu, D., Wan, L., Zhai, B., Yu, Y., et al. (2013) · Nature Cell Biology · doi:10.1038/ncb2860 · Cited by 256 · see citing works
Self-citationMultiple amino acid sensing inputs to mTORC1
Shimobayashi, M., & Hall, M. (2015) · Cell Research · doi:10.1038/cr.2015.146 · Cited by 216 · see citing works
Loss of Skeletal Muscle HIF-1α Results in Altered Exercise Endurance
Mason, S. D., Howlett, R. A., Kim, M. J., Olfert, I. M., Hogan, M. C., McNulty, W., Hickey, R. P., Wagner, P. D., Kahn, C. R., Giordano, F. J., et al. (2004) · PLoS Biology · doi:10.1371/journal.pbio.0020288 · Cited by 210 · see citing works
Single muscle fiber proteomics reveals unexpected mitochondrial specialization
Murgia, M., Nagaraj, N., Deshmukh, A. S., Zeiler, M., Cancellara, P., Moretti, I., Reggiani, C., Schiaffino, S., & Mann, M. (2015) · EMBO Reports · doi:10.15252/embr.201439757 · Cited by 202 · see citing works
Shah, O. J., & Hunter, T. R. (2006) · Molecular and Cellular Biology · doi:10.1128/mcb.01254-05 · Cited by 178 · see citing works
Erk regulation of pyruvate dehydrogenase flux through PDK4 modulates cell proliferationPreprint
Grassian, A. R., Metallo, C. M., Coloff, J. L., Stephanopoulos, G. N., & Brugge, J. S. (2011) · Genes & Development · doi:10.1101/gad.16771811 · Cited by 178 · see citing works
Differential response of skeletal muscles to mTORC1 signaling during atrophy and hypertrophy
Bentzinger, C. F., Lin, S., Romanino, K., Castets, P., Guridi, M., Summermatter, S., Handschin, C., Tintignac, L. A., Hall, M. N., & Rüegg, M. A. (2013) · Skeletal Muscle · doi:10.1186/2044-5040-3-6 · Cited by 153 · see citing works
Neklesa, T. K., & Davis, R. W. (2009) · PLoS Genetics · doi:10.1371/journal.pgen.1000515 · Cited by 151 · see citing works
Dokudovskaya, S., Waharte, F., Schlessinger, A., Pieper, U., Devos, D. P., Cristea, I. M., Williams, R., Salamero, J., Chait, B. T., Šali, A., et al. (2011) · Molecular & Cellular Proteomics · doi:10.1074/mcp.m110.006478 · Cited by 145 · see citing works
Doi, M., Yamaoka, I., Nakayama, M., Sugahara, K., & Yoshizawa, F. (2007) · American Journal of Physiology-Endocrinology and Metabolism · doi:10.1152/ajpendo.00609.2006 · Cited by 141 · see citing works
Activation of mTORC1 in skeletal muscle regulates whole-body metabolism through FGF21
Guridi, M., Tintignac, L. A. J., Lin, S., Kupr, B., Castets, P., & Rüegg, M. A. (2015) · Science Signaling · doi:10.1126/scisignal.aab3715 · Cited by 99 · see citing works
Wu, X., & Tu, B. P. (2011) · Molecular Biology of the Cell · doi:10.1091/mbc.e11-06-0525 · Cited by 98 · see citing works
Self-citationMyoD-cre transgenic mice: A model for conditional mutagenesis and lineage tracing of skeletal muscle
Chen, J. C. J., Mortimer, J., Marley, J., et al. (2005) · genesis · doi:10.1002/gene.20104 · Cited by 67 · see citing works
Self-citationHu, R., Huffman, K. E., Chu, M., Zhang, Y., Minna, J. D., & Yu, Y. (2016) · Journal of Proteome Research · doi:10.1021/acs.jproteome.5b00819 · Cited by 53 · see citing works
Self-citationLaxman, S., Sutter, B. M., Shi, L., & Tu, B. P. (2014) · Science Signaling · doi:10.1126/scisignal.2005948 · Cited by 52 · see citing works
Self-citationNutrient sensing by the mitochondrial transcription machinery dictates oxidative phosphorylation
Liu, L., Nam, M., Fan, W., Akie, T. E., Hoaglin, D. C., Gao, G., Keaney, J. F., & Cooper, M. P. (2014) · Journal of Clinical Investigation · doi:10.1172/jci69413 · Cited by 48 · see citing works
Regulation of Hematopoiesis and Methionine Homeostasis by mTORC1 Inhibitor NPRL2
Dutchak, P. A., Laxman, S., Estill, S., Wang, C.-S., Wang, Y., Wang, Y.-G., Bulut, G. B., Gao, J.-M., Huang, L., & Tu, B. P. (2015) · Cell Reports · doi:10.1016/j.celrep.2015.06.042 · Cited by 44 · see citing works
Self-citationKleinert, M., Liao, Y., Nelson, J. L., Bernard, J. R., Wang, W., & Ivy, J. L. (2011) · Journal of Applied Physiology · doi:10.1152/japplphysiol.01368.2010 · Cited by 29 · see citing works
GATOR1 regulates nitrogenic cataplerotic reactions of the mitochondrial TCA cycle
Chen, J., Sutter, B. M., Shi, L., & Tu, B. P. (2017) · Nature Chemical Biology · doi:10.1038/nchembio.2478 · Cited by 22 · see citing works
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Yoo, H. C., Yu, Y. C., Sung, Y., & Han, J. M. (2020) · Experimental & Molecular Medicine · doi:10.1038/s12276-020-00504-8 · Cited by 1,021 · see citing works
Self-citationCellular and molecular mechanisms of sarcopenia: The S100B perspective
Riuzzi, F., Sorci, G., Arcuri, C., Giambanco, I., Bellezza, I., Minelli, A., & Donato, R. (2018) · Journal of Cachexia Sarcopenia and Muscle · doi:10.1002/jcsm.12363 · Cited by 114 · see citing works
Mäntyselkä, S., Kolari, K., Baumert, P., Ylä-Outinen, L., Kuikka, L., Lahtonen, S., Permi, P., Wackerhage, H., Kalenius, E., Kivelä, R., et al. (2024) · American Journal of Physiology-Endocrinology and Metabolism · doi:10.1152/ajpendo.00151.2023 · Cited by 25 · see citing works
Stadhouders, L. E. M., Smith, J. A. B., Gabriel, B. M., Verbrugge, S. A. J., Hammersen, T. D., Kolijn, D., Vogel, I. S. P., Mohamed, A. D., de Wit, G. M. J., Offringa, C., et al. (2023) · Experimental Cell Research · doi:10.1016/j.yexcr.2023.113820 · Cited by 19 · see citing works
- Authors
- Dutchak, P. A., Estill-Terpack, S. J., Plec, A. A., Zhao, X., Yang, C., Chen, J., Ko, B., Deberardinis, R. J., Yu, Y., & Tu, B. P.
- Affiliations
- Université Laval (CA)
- The University of Texas Southwestern Medical Center (US)
- Children's Medical Center (US)
- Corresponding author
- Tu, Benjamin P.
- ORCID
- Venue
- Cell Reports
- Publisher
- Elsevier BV
- Published
- 2018-05
- Volume
- 23
- Issue
- 7
- Pages
- 1907-1914
- ISSN
- 2211-1247 (ISSN-L)
- PMC
- PMC6038807
- OpenAlex
- W2804014398
- Cited by
- 53
- References
- 47
- Citations by year
- 2026: 2 · 2025: 5 · 2024: 6 · 2023: 7 · 2022: 7 · 2021: 5 · 2020: 11 · 2019: 6 · 2018: 3
- FWCI
- 2.22
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- Locations
- Cell Reports (publishedVersion, cc-by-nc-nd)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion, cc-by-nc-nd)
- PubMed Central (acceptedVersion, cc-by-nc-nd)
- Funders
- Cancer Prevention and Research Institute of Texas (RP140655)
- Welch Foundation (I-1797)
- National Institutes of Health (R01 CA157996, R01 CA185169, R01 GM114160)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Metabolism, Diabetes, and Cancer
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › PI3K/AKT/mTOR signaling in cancer
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Muscle Physiology and Disorders
- Keywords
- GATOR1 complex, NPRL2, mTORC1, skeletal muscle, aerobic glycolysis, muscle fiber composition, fast-twitch glycolytic fibers, slow-twitch oxidative fibers, glucose tolerance, TCA cycle, anaplerotic pathway, mitochondrial function, muscle fiber size, running behavior
- MeSH terms
- Mechanistic Target of Rapamycin Complex 1, Aerobiosis, Amino Acids, Animals, Behavior, Animal, Citric Acid Cycle, Glycolysis, Mice, Inbred C57BL, Mice, Knockout, Muscle Fibers, Skeletal, Tumor Suppressor Proteins, Carbohydrate Metabolism
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