Glucose Metabolism Drives Histone Acetylation Landscape Transitions that Dictate Muscle Stem Cell Function

摘要

The impact of glucose metabolism on muscle regenerationremains unresolved. We identify glucosemetabolism as a crucial driver of histone acetylationand myogenic cell fate. We use single-cell mass cytometry(CyTOF) and flow cytometry to characterizethe histone acetylation and metabolic states ofquiescent, activated, and differentiating musclestem cells (MuSCs). We find glucose is dispensablefor mitochondrial respiration in proliferating MuSCs,so that glucose becomes available for maintaininghigh histone acetylation via acetyl-CoA. Conversely,quiescent and differentiating MuSCs increaseglucose utilization for respiration and have consequentlyreduced acetylation. Pyruvate dehydrogenase(PDH) activity serves as a rheostat for histoneacetylation and must be controlled for muscleregeneration. Increased PDH activity in proliferationincreases histone acetylation and chromatin accessibilityat genes that must be silenced for differentiationto proceed, and thus promotes self-renewal.These results highlight metabolism as a determinantof MuSC histone acetylation, fate, and function duringmuscle regeneration.