A1 Journal article (refereed)
Skeletal muscle hypertrophy rewires glucose metabolism : An experimental investigation and systematic review (2024)
Baumert, P., Mäntyselkä, S., Schönfelder, M., Heiber, M., Jacobs, M. J., Swaminathan, A., Minderis, P., Dirmontas, M., Kleigrewe, K., Meng, C., Gigl, M., Ahmetov, I. I., Venckunas, T., Degens, H., Ratkevicius, A., Hulmi, J. J., & Wackerhage, H. (2024). Skeletal muscle hypertrophy rewires glucose metabolism : An experimental investigation and systematic review. Journal of Cachexia, Sarcopenia and Muscle, 15(3), 989-1002. https://doi.org/10.1002/jcsm.13468
JYU authors or editors
Publication details
All authors or editors: Baumert, Philipp; Mäntyselkä, Sakari; Schönfelder, Martin; Heiber, Marie; Jacobs, Mika Jos; Swaminathan, Anandini; Minderis, Petras; Dirmontas, Mantas; Kleigrewe, Karin; Meng, Chen; et al.
Journal or series: Journal of Cachexia, Sarcopenia and Muscle
ISSN: 2190-5991
eISSN: 2190-6009
Publication year: 2024
Publication date: 14/05/2024
Volume: 15
Issue number: 3
Pages range: 989-1002
Publisher: Wiley-VCH Verlag
Publication country: Germany
Publication language: English
DOI: https://doi.org/10.1002/jcsm.13468
Publication open access: Openly available
Publication channel open access: Open Access channel
Publication is parallel published (JYX): https://jyx.jyu.fi/handle/123456789/94894
Web address of parallel published publication (pre-print): https://www.biorxiv.org/content/10.1101/2022.12.08.519580v3
Abstract
Proliferating cancer cells shift their metabolism towards glycolysis, even in the presence of oxygen, to especially generate glycolytic intermediates as substrates for anabolic reactions. We hypothesize that a similar metabolic remodelling occurs during skeletal muscle hypertrophy.
Methods
We used mass spectrometry in hypertrophying C2C12 myotubes in vitro and plantaris mouse muscle in vivo and assessed metabolomic changes and the incorporation of the [U-13C6]glucose tracer. We performed enzyme inhibition of the key serine synthesis pathway enzyme phosphoglycerate dehydrogenase (Phgdh) for further mechanistic analysis and conducted a systematic review to align any changes in metabolomics during muscle growth with published findings. Finally, the UK Biobank was used to link the findings to population level.
Results
The metabolomics analysis in myotubes revealed insulin-like growth factor-1 (IGF-1)-induced altered metabolite concentrations in anabolic pathways such as pentose phosphate (ribose-5-phosphate/ribulose-5-phosphate: +40%; P = 0.01) and serine synthesis pathway (serine: −36.8%; P = 0.009). Like the hypertrophy stimulation with IGF-1 in myotubes in vitro, the concentration of the dipeptide l-carnosine was decreased by 26.6% (P = 0.001) during skeletal muscle growth in vivo. However, phosphorylated sugar (glucose-6-phosphate, fructose-6-phosphate or glucose-1-phosphate) decreased by 32.2% (P = 0.004) in the overloaded muscle in vivo while increasing in the IGF-1-stimulated myotubes in vitro. The systematic review revealed that 10 metabolites linked to muscle hypertrophy were directly associated with glycolysis and its interconnected anabolic pathways. We demonstrated that labelled carbon from [U-13C6]glucose is increasingly incorporated by ~13% (P = 0.001) into the non-essential amino acids in hypertrophying myotubes, which is accompanied by an increased depletion of media serine (P = 0.006). The inhibition of Phgdh suppressed muscle protein synthesis in growing myotubes by 58.1% (P < 0.001), highlighting the importance of the serine synthesis pathway for maintaining muscle size. Utilizing data from the UK Biobank (n = 450 243), we then discerned genetic variations linked to the serine synthesis pathway (PHGDH and PSPH) and to its downstream enzyme (SHMT1), revealing their association with appendicular lean mass in humans (P < 5.0e-8).
Conclusions
Understanding the mechanisms that regulate skeletal muscle mass will help in developing effective treatments for muscle weakness. Our results provide evidence for the metabolic rewiring of glycolytic intermediates into anabolic pathways during muscle growth, such as in serine synthesis.
Keywords: glucose metabolism; musculoskeletal system; endurance training; metabolomics; lactates
Free keywords: lactate; metabolomics; resistance exercise; serine synthesis pathway; Warburg effect
Contributing organizations
Ministry reporting: Yes
VIRTA submission year: 2024
Preliminary JUFO rating: 2
