Baxter Laboratory for Stem Cell Biology, Department of Microbiology and Immunology, Institute for Stem Cell Biology and Regenerative Medicine, Stanford University School of Medicine, Stanford, CA 94305, USA.
Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
Cell Rep. 2019 Jun 25;27(13):3939-3955.e6. doi: 10.1016/j.celrep.2019.05.092.
The impact of glucose metabolism on muscle regeneration remains unresolved. We identify glucose metabolism as a crucial driver of histone acetylation and myogenic cell fate. We use single-cell mass cytometry (CyTOF) and flow cytometry to characterize the histone acetylation and metabolic states of quiescent, activated, and differentiating muscle stem cells (MuSCs). We find glucose is dispensable for mitochondrial respiration in proliferating MuSCs, so that glucose becomes available for maintaining high histone acetylation via acetyl-CoA. Conversely, quiescent and differentiating MuSCs increase glucose utilization for respiration and have consequently reduced acetylation. Pyruvate dehydrogenase (PDH) activity serves as a rheostat for histone acetylation and must be controlled for muscle regeneration. Increased PDH activity in proliferation increases histone acetylation and chromatin accessibility at genes that must be silenced for differentiation to proceed, and thus promotes self-renewal. These results highlight metabolism as a determinant of MuSC histone acetylation, fate, and function during muscle regeneration.
葡萄糖代谢对肌肉再生的影响仍未解决。我们发现葡萄糖代谢是组蛋白乙酰化和生肌细胞命运的关键驱动因素。我们使用单细胞质量细胞术（CyTOF）和流式细胞术来描述静息、激活和分化的肌肉干细胞（MuSCs）中的组蛋白乙酰化和代谢状态。我们发现葡萄糖对于增殖中的 MuSCs 的线粒体呼吸是可有可无的，因此葡萄糖可通过乙酰辅酶 A 用于维持高组蛋白乙酰化。相反，静息和分化的 MuSCs 增加葡萄糖用于呼吸，因此乙酰化减少。丙酮酸脱氢酶（PDH）活性作为组蛋白乙酰化的变阻器，必须进行控制以促进肌肉再生。增殖中 PDH 活性的增加增加了必须沉默以进行分化的基因的组蛋白乙酰化和染色质可及性，从而促进自我更新。这些结果强调了代谢是 MuSC 组蛋白乙酰化、命运和功能在肌肉再生过程中的决定因素。
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