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Title:

Metabolic remodeling during skeletal Muscle hypertrophy: role of glycolysis-derived intermediates in anabolic pathways

Document type:
Konferenzbeitrag
Contribution type:
Poster
Author(s):
Philipp Baumert, Sakari Mäntyselkä, Martin Schönfelder, Marie Heiber, Anandini Swaminathan, Petras Minderis; Mantas Dirmontas, Karin Kleigrewe, Chen Meng, Michael Gigl, Tomas Venckunas, Hans Degens, Aivaras Ratkevicius, Juha J. Hulmi & Henning Wackerhage
Abstract:
Introduction: Proliferating cancer cells shift their metabolism toward glycolysis even in the presence of oxygen to generate glycolytic intermediates as substrates for anabolic reactions. However, whether and how a controlled growing muscle reprograms its metabolism in a similar manner is poorly researched. We hypothesise that a similar metabolic remodelling occurs during 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. 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 muscle cells revealed altered metabolite concentrations in anabolic pathways such as in the pentose phosphate (ribose-5phosphate/ribulose-5-phosphate: +40%; p=0.01) and serine synthesis pathway (serine: -36.8%; p=0.009) to build up biomass, as well as in the hexosamine biosynthetic pathway that serves as a basis for the post-translational so-called Olinked glycosylation modification. L-carnosine and UDP-Nacetylgalactosamine metabolites were decreased and increased in both hypertrophied muscles in mice in vivo (-25.9% and +252%) as well as in C2C12 myotubes in vitro (-44.1% and +75.6%), respectively (all p<0.042). The systematic review showed that 12 of 20 identified metabolites associated with muscle hypertrophy were directly related to glycolysis and to its linked 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. The inhibition of the key enzyme phosphoglycerate dehydrogenase (Phgdh) supressed muscle protein synthesis by 74.9% (p=0.008) 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.
Book / Congress title:
16th international Conference of the Society on Cachexia, Sarcopenia & Muscle Wasting
Organization:
Society on Cachexia, Sarcopenia & Muscle Wasting
Date of congress:
17-19 Juni in Stockholm
Publisher:
Journal of Cachexia, Sarcopenia and Muscle
Date of publication:
17.06.2023
Year:
2023
Quarter:
2. Quartal
Year / month:
2023-06
Month:
Jun
Pages:
100
Covered by:
Web of Science
Impact Factor:
12,036
Reviewed:
ja
Language:
en
Publication format:
WWW
Semester:
SS 23
TUM Institution:
Sportbiologie
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