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Title:

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

Document type:
Zeitschriftenaufsatz
Author(s):
P. Baumert, S. Mäntyselkä, M. Schönfelder, M. Heiber, M.J. Jacobs, A. Swaminathan, P. Minderis; M. Dirmontas, K. Kleigrewe, C. Meng, M. Gigl, T. Venckunas, H. Degens, A. Ratkevicius, JJ. Hulmi, H. Wackerhage
Abstract:
Objective: Proliferating cancer cells shift their metabolism toward glycolysis even in the presence of oxygen to generate glycolytic intermediates as substrates for anabolic reactions. We hypothesise that a similar metabolic remodelling occurs during skeletal muscle hypertrophy. Methods: We used mass spectrometry in hypertrophying muscles both in differentiated 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. We performed enzyme inhibition for further mechanistic analysis and a systematic review to align any changes in metabolomics during muscle growth with previous findings. Results: The metabolomics analysis in C2C12 myotubes revealed IGF-1 induced altered metabolite concentrations in anabolic pathways such as in the pentose phosphate (ribose-5-phosphate/ribulose-5-phosphate: +40%; p=0.01) and serine synthesis pathway (serine: -36.8%; p=0.009) to build up biomass. Similar to 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 concentration showed contrasting trends, decreasing by 32.2% (p=0.005) in the overloaded muscle in vivo, whilst increasing in the IGF-1 stimulated myotubes in vitro. The systematic review revealed that 11 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 the key enzyme phosphoglycerate dehydrogenase (Phgdh) supressed muscle protein synthesis by 58.1% (p<0.001). This resulted in 36.8% lower total muscle cell protein concentration (p<0.001) 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.
Dewey Decimal Classification:
570 Biowissenschaften, Biologie
Journal title:
Journal of Cachexia, Sarcopenia and Muscle
Year:
2024
Year / month:
2024-03
Quarter:
1. Quartal
Month:
Mar
Covered by:
Web of Science
Reviewed:
ja
Language:
en
Fulltext / DOI:
doi:10.1002/jcsm.13468
Publisher:
Wiley
Impact Factor:
12,511
Scimago Quartil:
Q1
Notes:
SCImago Journal & Country Rank
Semester:
WS 23-24
TUM Institution:
Sportbiologie
Format:
Bild/Text
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