{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,14]],"date-time":"2026-09-14T18:15:09Z","timestamp":1789409709138,"version":"build-2803163510"},"reference-count":40,"publisher":"Wiley","issue":"3","license":[{"start":{"date-parts":[[2024,5,14]],"date-time":"2024-05-14T00:00:00Z","timestamp":1715644800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100000780","name":"European Commission","doi-asserted-by":"publisher","award":["754462"],"award-info":[{"award-number":["754462"]}],"id":[{"id":"10.13039\/501100000780","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100010781","name":"Diabetes-Stiftung","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100010781","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["J cachexia sarcopenia muscle"],"published-print":{"date-parts":[[2024,6]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>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.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>\n                      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\u2010\n                      <jats:sup>13<\/jats:sup>\n                      C\n                      <jats:sub>6<\/jats:sub>\n                      ]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.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      The metabolomics analysis in myotubes revealed insulin\u2010like growth factor\u20101 (IGF\u20101)\u2010induced altered metabolite concentrations in anabolic pathways such as pentose phosphate (ribose\u20105\u2010phosphate\/ribulose\u20105\u2010phosphate: +40%;\n                      <jats:italic>P<\/jats:italic>\n                      \u00a0=\u00a00.01) and serine synthesis pathway (serine: \u221236.8%;\n                      <jats:italic>P<\/jats:italic>\n                      \u00a0=\u00a00.009). Like the hypertrophy stimulation with IGF\u20101 in myotubes in vitro, the concentration of the dipeptide\n                      <jats:sc>l<\/jats:sc>\n                      \u2010carnosine was decreased by 26.6% (\n                      <jats:italic>P<\/jats:italic>\n                      \u00a0=\u00a00.001) during skeletal muscle growth in vivo. However, phosphorylated sugar (glucose\u20106\u2010phosphate, fructose\u20106\u2010phosphate or glucose\u20101\u2010phosphate) decreased by 32.2% (\n                      <jats:italic>P<\/jats:italic>\n                      \u00a0=\u00a00.004) in the overloaded muscle in vivo while increasing in the IGF\u20101\u2010stimulated 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\u2010\n                      <jats:sup>13<\/jats:sup>\n                      C\n                      <jats:sub>6<\/jats:sub>\n                      ]glucose is increasingly incorporated by ~13% (\n                      <jats:italic>P<\/jats:italic>\n                      \u00a0=\u00a00.001) into the non\u2010essential amino acids in hypertrophying myotubes, which is accompanied by an increased depletion of media serine (\n                      <jats:italic>P<\/jats:italic>\n                      \u00a0=\u00a00.006). The inhibition of Phgdh suppressed muscle protein synthesis in growing myotubes by 58.1% (\n                      <jats:italic>P<\/jats:italic>\n                      \u00a0&lt;\u00a00.001), highlighting the importance of the serine synthesis pathway for maintaining muscle size. Utilizing data from the UK Biobank (\n                      <jats:italic>n<\/jats:italic>\n                      \u00a0=\u00a0450\u00a0243), we then discerned genetic variations linked to the serine synthesis pathway (\n                      <jats:italic>PHGDH<\/jats:italic>\n                      and\n                      <jats:italic>PSPH<\/jats:italic>\n                      ) and to its downstream enzyme (\n                      <jats:italic>SHMT1<\/jats:italic>\n                      ), revealing their association with appendicular lean mass in humans (\n                      <jats:italic>P<\/jats:italic>\n                      \u00a0&lt;\u00a05.0e\u20108).\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>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.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1002\/jcsm.13468","type":"journal-article","created":{"date-parts":[[2024,5,14]],"date-time":"2024-05-14T05:48:14Z","timestamp":1715665694000},"page":"989-1002","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":40,"title":["Skeletal muscle hypertrophy rewires glucose metabolism: An experimental investigation and systematic review"],"prefix":"10.1002","volume":"15","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-5463-1954","authenticated-orcid":false,"given":"Philipp","family":"Baumert","sequence":"first","affiliation":[{"name":"School of Medicine and Health Technical University of Munich  Munich Germany"},{"name":"Research Institute for Sport and Exercise Sciences Liverpool John Moores University  Liverpool 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