Abstract
Unlike the glucocorticoid receptor α (GRα), GR β (GRβ) has a truncated ligand-binding domain that prevents glucocorticoid binding, implicating GRα as the mediator of glucocorticoid-induced skeletal muscle loss. Because GRβ causes glucocorticoid resistance, targeting GRβ may be beneficial in impairing muscle loss as a result of GRα activity. The purpose of this study was to determine how the overexpression of GRβ 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 GRβ 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. GRβ overexpression increased mRNA levels of muscle regulatory factors and enhanced proliferation in myoblasts. GRβ overexpressing myotubes had an increased fusion index. Myotubes overexpressing GRβ 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 GRβ may serve as a pharmacological target for skeletal muscle growth and protection from glucocorticoid-induced catabolic signaling. Increasing GRβ levels in skeletal muscle may cause a state of glucocorticoid resistance, stabilizing muscle mass during exposure to high doses of glucocorticoids.
Highlights
Chronic glucocorticoid (GC) treatment and prolonged elevations of endogenous GC production cause skeletal muscle atrophy and reduce the adaptive response of skeletal muscle to injurious and atrophic events [1,2,3,4]
We have previously shown that the mouse muscle cell line C2C12 expresses both glucocorticoid receptor α (GRα) and glucocorticoid receptor (GR) β (GRβ) [20]
We showed in the mouse embryonic fibroblast (MEF) cells that GRβ mRNA [9] and protein [20] increased in response to insulin
Summary
Chronic glucocorticoid (GC) treatment and prolonged elevations of endogenous GC production cause skeletal muscle atrophy and reduce the adaptive response of skeletal muscle to injurious and atrophic events [1,2,3,4]. While the physiological roles of GRβ are not completely understood, increased GRβ expression has been linked to GC resistance in patients suffering from severe asthma [12,13,14,15], leukemia [16], cancer [17], and inflammation [18], which reduces the therapeutic potential of GCs. transcriptome analysis of cultured cells overexpressing GRβ indicated intrinsic transcriptional activities independent of GRα [19]. We recently demonstrated that GRβ positively regulates cell proliferation by attenuating phosphatase and tensin homolog deleted on chromosome 10 (PTEN) expression and by increasing Akt phosphorylation in 3T3-L1 cells [20]. Akt regulates embryonic and fetal growth, which suggests that GRβ may have a predominant role in development and proliferation. GRβ has been shown to regulate the growth of glioblastoma [21] and prostate cancer cells [22] as well
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