Skeletal muscle hypertrophy rewires glucose metabolism in mice: an experimental investigation and systematic review

Objective Proliferating cancer cells shift their metabolism to anaerobic glycolysis even in the presence of oxygen to generate glycolytic intermediates as substrates for anabolic reactions. We hypothesise that a similar metabolic remodelling also occurs during physiological skeletal muscle hypertrophy. Methods We used mass spectrometry in hypertrophying muscles both in C2C12 muscle cells in vitro and plantaris mice muscle in vivo and assessed metabolomic changes and the incorporation of stable isotope [U-13C6]glucose tracer compared with non-treated controls. We also performed enzyme inhibition for further mechanistic analysis and a systematic review to align any changes in metabolomics during muscle growth with previous findings. Results Both our metabolomics analysis and the systematic review reveal altered metabolite concentrations in anabolic pathways such as in the pentose phosphate and serine synthesis pathway to build up biomass, as well as in the hexosamine biosynthetic pathway that serves as a basis for the post-translational so-called O-linked glycosylation modification. We further demonstrated that labelled carbon from [U-13C6]glucose is increasingly incorporated into the non-essential amino acids in hypertrophying myotubes. The inhibition of the key enzyme phosphoglycerate dehydrogenase (Phgdh) supresses muscle protein synthesis by 75% highlighting the importance of the serine pathway for maintaining muscle size. Conclusion Understanding the mechanisms that regulates skeletal muscle mass will help in developing effective treatments against muscle weakness. Our results provide evidence for metabolic rewiring of glycolytic intermediates into anabolic pathways during muscle growth, such as in the serine synthesis and hexosamine biosynthetic pathways.