A1 Journal article (refereed)
Serine synthesis pathway enzyme PHGDH is critical for muscle cell biomass, anabolic metabolism, and mTORC1 signaling (2024)
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
JYU authors or editors
Publication details
All authors or editors: Mäntyselkä, Sakari; Kolari, Kalle; Baumert, Philipp; Ylä-Outinen, Laura; Kuikka, Lauri; Lahtonen, Suvi; Permi, Perttu; Wackerhage, Henning; Kalenius, Elina; Kivelä, Riikka; et al.
Journal or series: American Journal of Physiology : Endocrinology and Metabolism
ISSN: 0193-1849
eISSN: 1522-1555
Publication year: 2024
Publication date: 22/11/2023
Volume: 326
Issue number: 1
Pages range: E73-E91
Publisher: American Physiological Society
Publication country: United States
Publication language: English
DOI: https://doi.org/10.1152/ajpendo.00151.2023
Publication open access: Not open
Publication channel open access:
Publication is parallel published (JYX): https://jyx.jyu.fi/handle/123456789/92473
Abstract
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.
Keywords: muscle cells; cell physiology; metabolism; glucose metabolism; muscle mass; cell signaling; enzymes
Free keywords: glycolysis; metabolic reprogramming; mTORC1; protein synthesis; Warburg effect
Contributing organizations
Related projects
- Warburg-ilmiön ja glykolyysin rinnakkaisreittien merkitys lihaskoon säätelyssä ja aineenvaihduntatuotteiden erityksessä
- Mäntyselkä, Sakari
- Emil Aaltonen Foundation
Ministry reporting: Yes
Reporting Year: 2023
Preliminary JUFO rating: 2
- School of Wellbeing (University of Jyväskylä JYU) JYU.Well
- Nanoscience Center (Department of Physics PHYS, JYFL) (Faculty of Mathematics and Science) (Department of Chemistry CHEM) (Department of Biological and Environmental Science BIOENV) NSC
- Organic Chemistry (Department of Chemistry CHEM) KEO
- Analytical Chemistry (Department of Chemistry CHEM)
- Exercise Physiology (Faculty of Sport and Health Sciences LTK, SPORT) LFY