The glucocorticoid receptor is a critical regulator of muscle satellite cell quiescence.

Glucocorticoids are powerful anti-inflammatory medications that are associated with muscle atrophy. The effect of glucocorticoids in myofibers is well-studied, yet the role of the glucocorticoid receptor (GR), the primary mediator of glucocorticoid transcriptional responses, and the impact of glucocorticoid signalling in muscle stem cells (MuSCs), the adult progenitors responsible for regeneration, remain unknown. We developed a conditional null mouse model to knock out glucocorticoid receptor (GR) expression in MuSCs (GRMuSC-/-) and established that while GR is dispensable for muscle regeneration, it is a critical regulator of MuSC homeostasis. Loss of GR significantly increased cycling MuSCs as compared to controls in injury-naive mice and on single EDL myofiber cultures, and as such, loss of GR in MuSCs leads to precocious activation and subsequent proliferation as compared to controls. Bulk RNA-sequencing from in situ fixed MuSCs from injury-naive GRMuSC-/- muscle identified a gene signature consistent with cells that have exited quiescence and undergone activation, with evidence of sexual dimorphism. Using ATAC-seq and footprinting we identify putative GR targets that promote quiescence. Thus, we advance the GR as a previously unrecognized crucial transcriptional regulator of gene expression in MuSCs whose activity is highest in quiescent cells and is essential to maintain that state.