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BACKGROUND: 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 synt

Methionine restriction (MR) reduces inflammation and increases longevity. We studied the effects of MR (0.17% kCal methionine, 10% kCal fat) and MR + high-fat diet (HFD) (0.17% methionine, 45% kCal fat) and overload-induced hypertrophy on inflammation, angiogenesis and mitochondrial activity in the hind-limb muscle in 10- and 26-month-old male C57BL/6J mice. Plasma IL-6 concentrations were higher in old compared to young mice. M. plantaris hypertrophy was accompanied by increased p-Akt, without a significant change in Akt and VEGF levels. In young mice on a HFD or MR + HFD diet the SDH activity was higher than in those from mice on other diets, irrespective of overload. There were no significant differences in total NAD concentration in the m. gastrocnemius. MR enhanced the skeletal muscle hypertrophic response in old age that was accompanied with an increase in p-Akt without significant changes in muscle oxidative capacity, low-grade systemic inflammation, NAD, VEGF or Akt levels.

The age-related decline in muscle function is aggravated by a high-fat diet (HFD) induced increase in fat mass. The hypothesis is that a HFD leads to a faster accumulation of intramyocellular lipids (IMCL) and an earlier onset of muscle dysfunction in old than in young-adult individuals. The IMCL accumulation is attenuated in young-adult organisms by an elevated oxidative capacity. Methionine restriction enhances mitochondrial biogenesis and is promising to combat obesity across the ages.