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 a branch of 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 MuSC activation and expansion of myogenic progenitors through production of the metabolite α-ketoglutarate (α-KG) and α-KG-generated glutamine. Psat1 ablation resulted in defective expansion of MuSCs and impaired regeneration. Psat1, α-KG, and glutamine were reduced in MuSCs of old mice. α-KG or glutamine re-established appropriate muscle regeneration of adult conditional Psat1^−/− mice and of old mice. These findings contribute insights into the metabolic role of Psat1 during muscle regeneration and suggest α-KG and glutamine as potential therapeutic interventions to ameliorate muscle regeneration during aging.

中文翻译：

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Psat1产生的α-酮戊二酸和谷氨酰胺促进肌肉干细胞活化和再生

通过满足生物能需求、产生生物量并提供作为染色质修饰剂辅助因子的代谢物，代谢调节成体干细胞生物学。在这里，我们报道了糖酵解的一个分支，即丝氨酸生物合成途径（SBP），在再生肌肉干细胞（MuSC）中被激活。基因失活和代谢组学表明，Psat1（三种 SBP 酶之一）通过产生代谢物 α-酮戊二酸 (α-KG) 和 α-KG 生成的谷氨酰胺来控制 MuSC 激活和肌源性祖细胞的扩增。Psat1消融导致 MuSC 扩增缺陷和再生受损。年老小鼠 MuSC 中的 Psat1、α-KG 和谷氨酰胺减少。 α-KG 或谷氨酰胺重建了成年条件性Psat1 ^−/−小鼠和老年小鼠的适当肌肉再生。这些发现有助于深入了解 Psat1 在肌肉再生过程中的代谢作用，并表明 α-KG 和谷氨酰胺可以作为改善衰老过程中肌肉再生的潜在治疗干预措施。