A1 Alkuperäisartikkeli tieteellisessä aikakauslehdessä
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-tekijät tai -toimittajat


Julkaisun tiedot

Julkaisun kaikki tekijät tai toimittajat: Mäntyselkä, Sakari; Kolari, Kalle; Baumert, Philipp; Ylä-Outinen, Laura; Kuikka, Lauri; Lahtonen, Suvi; Permi, Perttu; Wackerhage, Henning; Kalenius, Elina; Kivelä, Riikka; et al.

Lehti tai sarja: American Journal of Physiology : Endocrinology and Metabolism

ISSN: 0193-1849

eISSN: 1522-1555

Julkaisuvuosi: 2024

Ilmestymispäivä: 22.11.2023

Volyymi: 326

Lehden numero: 1

Artikkelin sivunumerot: E73-E91

Kustantaja: American Physiological Society

Julkaisumaa: Yhdysvallat (USA)

Julkaisun kieli: englanti

DOI: https://doi.org/10.1152/ajpendo.00151.2023

Julkaisun avoin saatavuus: Ei avoin

Julkaisukanavan avoin saatavuus: 

Julkaisu on rinnakkaistallennettu (JYX): https://jyx.jyu.fi/handle/123456789/92473


Tiivistelmä

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.


YSO-asiasanat: lihassolut; solufysiologia; aineenvaihdunta; glukoosiaineenvaihdunta; lihasmassa; soluviestintä; entsyymit

Vapaat asiasanat: glycolysis; metabolic reprogramming; mTORC1; protein synthesis; Warburg effect


Liittyvät organisaatiot


Hankkeet, joissa julkaisu on tehty


OKM-raportointi: Kyllä

Raportointivuosi: 2023

Alustava JUFO-taso: 2


Viimeisin päivitys 2024-13-05 klo 18:06