Metabolism regulates muscle stem cell self renewal by connecting the microenvironment and histone acetylation

Ly CH1, Su S2, Tian L2, Zalcenstein D2, Naik S2, Ritchie M2, Lynch GS1 and Ryall JG1

  1. Centre for Muscle Research, Department of Physiology, The University of Melbourne.
  2. The Walter and Eliza Hall Institute of Medical Research.

Skeletal muscle contains a resident population of somatic stem cells which are capable of both self-renewal and differentiation. The signals that regulate this important decision have yet to be fully elucidated. Here we use scRNAseq to identify the innate metabolic signature of muscle stem cells. We show that committed muscle progenitor cells exhibit an enrichment of glycolytic and TCA cycle genes and that extracellular carbohydrate availability regulates intracellular citrate levels and global histone acetylation. Muscle stem cells exposed to a reduced (or altered) carbohydrate environment demonstrate reduced global histone acetylation and transcription of myogenic determination factors (including myod1). Importantly, reduced carbohydrate availability was directly linked to increased rates of asymmetric division and muscle stem cell self-renewal. Our results reveal an important role for the extracellular metabolic environment in the decision to undergo self-renewal or myogenic commitment, suggesting local metabolite production may be a therapeutic target to improve muscle regeneration.