Serine synthesis pathway enzyme PHGDH is critical for muscle cell biomass, anabolic metabolism, and mTORC1 signaling
Mäntyselkä, S., Kolari, K., Baumert, P., Ylä-Outinen, L., Kuikka, L., Lahtonen, S., Permi, P., Wackerhage, H., Kalenius, E., Kivelä, R., & Hulmi, J. J. (2024). Serine synthesis pathway enzyme PHGDH is critical for muscle cell biomass, anabolic metabolism, and mTORC1 signaling. American Journal of Physiology : Endocrinology and Metabolism, 326(1), E73-E91. https://doi.org/10.1152/ajpendo.00151.2023
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2024Discipline
Epäorgaaninen ja analyyttinen kemiaNanoscience CenterLiikuntafysiologiaHyvinvoinnin tutkimuksen yhteisöOrgaaninen kemiaAnalyyttinen kemiaInorganic and Analytical ChemistryNanoscience CenterExercise PhysiologySchool of WellbeingOrganic ChemistryAnalytical ChemistryAccess restrictions
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© 2023, American Journal of Physiology-Endocrinology and Metabolism
Cells use glycolytic intermediates for anabolism e.g., via the serine synthesis and pentose phosphate pathways. However, we still understand poorly how these metabolic pathways contribute to skeletal muscle cell biomass generation. The first aim of this study was therefore to identify enzymes that limit protein synthesis, myotube size, and proliferation in skeletal muscle cells. We inhibited key enzymes of glycolysis, the pentose phosphate pathway, and serine synthesis pathway to evaluate their importance in C2C12 myotube protein synthesis. Based on the results of this first screen, we then focused on the serine synthesis pathway enzyme phosphoglycerate dehydrogenase (PHGDH). We used two different PHGDH inhibitors and mouse C2C12 and human primary muscle cells to study the importance and function of the PHGDH. Both myoblasts and myotubes incorporated glucose-derived carbon into proteins, RNA, and lipids and we showed that PHGDH is essential in these processes. PHGDH inhibition decreased protein synthesis, myotube size, and myoblast proliferation without cytotoxic effects. The decreased protein synthesis in response to PHGDH inhibition appears to occur mainly mTORC1 dependently as was evident from experiments with insulin-like growth factor 1 and rapamycin. Further metabolomics analyses revealed that PHGDH inhibition accelerated glycolysis and altered amino acid, nucleotide, and lipid metabolism. Lastly, we found that supplementing an antioxidant and redox modulator N-acetylcysteine partially rescued the decreased protein synthesis and mTORC1 signaling during PHGDH inhibition. The data suggest that PHGDH activity is critical for skeletal muscle cell biomass generation from glucose, and that it regulates protein synthesis and mTORC1 signaling.
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This work was supported by the Academy of Finland Profi5 funding (Physical ACTivity and health during the human life-Span 2; PACTS2, 301824) to the Faculty of Sport and Health Sciences and the Emil Aaltonen Foundation (S.M.), Finnish Cultural Foundation (K.K. and J.J.H), University of Jyväskylä Starting grant (J.J.H. and R.K.), and University of Jyväskylä Visiting Fellow grant (P.B.). P.B. as part of the EuroTech Postdoc Programme, was also co-funded by the European Commission under its framework programme Horizon 2020 (754462). ...License
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