The glucocorticoid receptor coordinates myofiber-selective transcriptional networks

Muscle fibers have the capacity to modulate their size in response to hormones, including glucocorticoids. Their effects are mediated by the ubiquitously expressed glucocorticoid receptor (GR). However, GR-mediated transcriptional regulation in skeletal muscle at physiological glucocorticoid levels remains elusive. Our study reveals an increased expression of numerous anabolic factors in GR-deficient myofibers, and a reduced expression of antianabolic factors, leading to fiber hypertrophy. Genome-wide analyses demonstrate that myofiber GR controls broad gene networks by binding to glucocorticoid response elements (GREs) at enhancers. Moreover, we provide topological and molecular insights into the chromatin landscape of GR-controlled genes in myofibers. We demonstrate that cooperative binding of GR with the transcription factors Myod1 and Foxf2 in enhancer regions, in collaboration with Nrf1 at promoters, plays a key role in the negative regulation of muscle mass. Thus, these results open new perspectives to counteract muscle weakness in various diseases. Gene expression profiling was performed on total RNA isolated from control and GR(i)skm-/- gastrocnemius muscles