Metabolic Promotion of Adult and Aging Skeletal Muscle Regeneration by the Serine Biosynthesis Pathway [bulkRNA]

By satisfying bioenergetic demands, generating biomass, and providing metabolites serving as cofactors for chromatin modifiers, metabolism regulates adult stem cell biology. Here, we report that, branching off from glycolysis, the serine biosynthesis pathway (SBP) is activated in regenerating muscle stem cells (MuSCs). Gene inactivation and metabolomics revealed that Psat1, one of the three SBP enzymes, controls MuSCs activation and expansion of myogenic progenitors through production of the metabolite a-ketoglutarate (a-KG) and the a-KG-generated amino acid glutamine. Genetic ablation of Psat1 in MuSCs resulted in defective expansion of MuSCs and impaired regeneration. Psat1, a-KG, and glutamine were reduced in MuSCs of old mice and myoblasts of old individuals. a-KG or glutamine re-established appropriate muscle regeneration of adult Psat1-/- mice, old mice, and improved proliferation of old human myoblasts. These findings contribute insights into the metabolic role of Psat1 during muscle regeneration and suggest a-KG and glutamine as potential therapeutic interventions to ameliorate muscle regeneration during aging. Overall design: total RNA was extracted with Trizol from Ctrl and Psat1cKO myoblasts. 500ng of RNA was used to generate poly (A)+ mRNA libraries using NEBNext Ultra II Library preparation kit