Laboratory of Muscle Stem Cells and Gene Regulation, National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Institutes of Health, Bethesda, Maryland 20892, USA.
Biodata Mining and Discovery Section, National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Institutes of Health, Bethesda, Maryland 20892, USA.
Genes Dev. 2024 Mar 22;38(3-4):151-167. doi: 10.1101/gad.351428.123.
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. 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 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.
通过满足生物能量需求、生成生物量以及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，我们报告说，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 (MuSCs) 中被激活。基因失活和代谢组学揭示了 SBP 的三种酶之一 Psat1 通过产生代谢物 α-酮戊二酸 (α-KG) 和由 α-KG 生成的谷氨酰胺来控制 MuSC 的激活和肌源性祖细胞的扩增。Psat1 的缺失导致 MuSCs 的扩增缺陷和再生受损。MuSCs 中的 Psat1、α-KG 和谷氨酰胺减少了老年小鼠的 MuSCs。α-KG 或谷氨酰胺重建了成年条件性 小鼠和老年小鼠的适当肌肉再生。这些发现为肌肉再生过程中 Psat1 的代谢作用提供了深入了解，并表明 α-KG 和谷氨酰胺可能是改善衰老过程中肌肉再生的潜在治疗干预措施。
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