Metabolic regulation of muscle stem cell epigenetic landscape during regeneration

Muscle is known to be a highly glycolytic tissue, yet the impact of glucose metabolism in muscle stem cell function remains unresolved. Here we use Mass Cytometry (CyTOF) to capture changes in histone acetylation profiles at the single cell level in vivo following injury. We demonstrate that MuSCs transiently increase histone acetylation upon activation, followed by global loss upon commitment. The switch to a committed state is driven by glucose metabolism through pyruvate dehydrogenase (PDH), which fuels histone acetylation via production of acetyl-CoA. Pharmacological or genetic activation of PDH results in increased histone acetylation and impedes myogenic differentiation. Moreover, mice lacking PDH inhibitory kinases, PDK2 and PDK4, accumulate uncommitted satellite cells and exhibit impaired muscle regeneration. These studies identify PDH as a previously unrecognized dynamic metabolic mediator of epigenetic state crucial to myogenic commitment and regeneration. Overall design: Fresh versus 48hr cultured muscle stem cells(MuSCs) were sequenced by RNASeq. 3 replicates (F1-3) of freshly isolated MuSCs were run independently, while 2 replicates (F4-5) were run on the same lane as the cultured (C1-3) replicates.