IJMS, Vol. 17, Pages 232: Overexpression of Glucocorticoid Receptor ? Enhances Myogenesis and Reduces Catabolic Gene Expression (International Journal of Molecular Sciences)

Unlike the glucocorticoid receptor ? (GR?), GR ? (GR?) has a truncated ligand-binding domain that prevents glucocorticoid binding, implicating GR? as the mediator of glucocorticoid-induced skeletal muscle loss. Because GR? causes glucocorticoid resistance, targeting GR? may be beneficial in impairing muscle loss as a result of GR? activity. The purpose of this study was to determine how the overexpression of GR? affects myotube formation and dexamethasone (Dex) responsiveness. We measured GR isoform expression in C2C12 muscle cells in response to Dex and insulin, and through four days of myotube formation. Next, lentiviral-mediated overexpression of GR? in C2C12 was performed, and these cells were characterized for cell fusion and myotube formation, as well as sensitivity to Dex via the expression of ubiquitin ligases. GR? overexpression increased mRNA levels of muscle regulatory factors and enhanced proliferation in myoblasts. GR? overexpressing myotubes had an increased fusion index. Myotubes overexpressing GR? had lower forkhead box O3 (Foxo3a) mRNA levels and a blunted muscle atrophy F-box/Atrogen-1 (MAFbx) and muscle ring finger 1 (MuRF1) response to Dex. We showed that GR? may serve as a pharmacological target for skeletal muscle growth and protection from glucocorticoid-induced catabolic signaling. Increasing GR? levels in skeletal muscle may cause a state of glucocorticoid resistance, stabilizing muscle mass during exposure to high doses of glucocorticoids.