title: Overexpression of Glucocorticoid Receptor β Enhances Myogenesis and Reduces Catabolic Gene Expression.
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.
authors.affiliation: Center for Hypertension and Personalized Medicine, Department of Physiology and Pharmacology, University of Toledo College of Medicine, Toledo, OH 43614, USA. terry.hinds@utoledo.edu.
authors.forename: Terry D
authors.initials: TD
authors.lastname: Hinds
authors.affiliation: Laboratory of Systems Physiology, Department of Kinesiology, University of North Carolina Charlotte, Charlotte, NC 28223, USA. bpeck3@uncc.edu.
authors.forename: Bailey
authors.initials: B
authors.lastname: Peck
authors.affiliation: Laboratory of Systems Physiology, Department of Kinesiology, University of North Carolina Charlotte, Charlotte, NC 28223, USA. eshek@uncc.edu.
authors.forename: Evan
authors.initials: E
authors.lastname: Shek
authors.affiliation: Laboratory of Systems Physiology, Department of Kinesiology, University of North Carolina Charlotte, Charlotte, NC 28223, USA. sstroup4@uncc.edu.
authors.forename: Steven
authors.initials: S
authors.lastname: Stroup
authors.affiliation: Laboratory of Systems Physiology, Department of Kinesiology, University of North Carolina Charlotte, Charlotte, NC 28223, USA. jhinso47@uncc.edu.
authors.forename: Jennifer
authors.initials: J
authors.lastname: Hinson
authors.affiliation: Laboratory of Systems Physiology, Department of Kinesiology, University of North Carolina Charlotte, Charlotte, NC 28223, USA. sarthur8@uncc.edu.
authors.forename: Susan
authors.initials: S
authors.lastname: Arthur
authors.affiliation: Laboratory of Systems Physiology, Department of Kinesiology, University of North Carolina Charlotte, Charlotte, NC 28223, USA. jmarin10@uncc.edu.
authors.forename: Joseph S
authors.initials: JS
authors.lastname: Marino
mesh_terms: D000818:Animals; D002454:Cell Differentiation / Q000187:drug effects / Q000235:genetics; D002460:Cell Line; D003907:Dexamethasone / Q000494:pharmacology; D004734:Energy Metabolism / Q000187:drug effects / Q000235:genetics*; D015870:Gene Expression; D005786:Gene Expression Regulation / Q000187:drug effects; D007328:Insulin / Q000378:metabolism / Q000494:pharmacology; D051379:Mice; D024510:Muscle Development / Q000235:genetics*; D018485:Muscle Fibers, Skeletal / Q000166:cytology / Q000378:metabolism; D032446:Myoblasts / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D020033:Protein Isoforms; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D011965:Receptors, Glucocorticoid / Q000235:genetics*
chemical_list: D007328:Insulin; D020033:Protein Isoforms; D012333:RNA, Messenger; D011965:Receptors, Glucocorticoid; C121943:glucocorticoid receptor beta; D003907:Dexamethasone
keywords: GRα 5; GRβ 4; MAFbx 7; MuRF1 8; atrophy 6; dexamethasone 9; glucocorticoid receptor α 2; glucocorticoid receptor β 3; myogenesis