title: Dexamethasone-induced muscular atrophy is mediated by functional expression of connexin-based hemichannels.
abstract: Long-term treatment with high glucocorticoid doses induces skeletal muscle atrophy. However, the molecular mechanism of such atrophy remains unclear. We evaluated the possible involvement of connexin-based hemichannels (Cx HCs) in muscle atrophy induced by dexamethasone (DEX), a synthetic glucocorticoid, on control (Cx43(fl/fl)Cx45(fl/fl)) and Cx43/Cx45 expression-deficient (Cx43(fl/fl)Cx45(fl/fl):Myo-Cre) skeletal myofibers. Myofibers of Cx43(fl/fl)Cx45(fl/fl) mice treated with DEX (5h) expressed several proteins that form non-selective membrane channels (Cx39, Cx43, Cx45, Panx1, P2X7 receptor and TRPV2). After 5h DEX treatment in vivo, myofibers of Cx43(fl/fl)Cx45(fl/fl) mice showed Evans blue uptake, which was absent in myofibers of Cx43(fl/fl)Cx45(fl/fl):Myo-Cre mice. Similar results were obtained in vitro using ethidium as an HC permeability probe, and DEX-induced dye uptake in control myofibers was blocked by P2X7 receptor inhibitors. DEX also induced a significant increase in basal intracellular Ca(2+) signal and a reduction in resting membrane potential in Cx43(fl/fl)Cx45(fl/fl) myofibers, changes that were not elicited by myofibers deficient in Cx43/Cx45 expression. Moreover, treatment with DEX induced NFκB activation and increased mRNA levels of TNF-α in control but not in Cx43/Cx45 expression-deficient myofibers. Finally, a prolonged DEX treatment (7days) increased atrogin-1 and Murf-1 and reduced the cross sectional area of Cx43(fl/fl)Cx45(fl/fl) myofibers, but these parameters remained unaffected in Cx43(fl/fl)Cx45(fl/fl):Myo-Cre myofibers. Therefore, DEX-induced expression of Cx43 and Cx45 plays a critical role in early sarcolemma changes that lead to atrophy. Consequently, this side effect of chronic glucocorticoid treatment might be avoided by co-administration with a Cx HC blocker.
authors.affiliation: Institute of Biomedical Sciences, Faculty of Medicine, University of Chile, Santiago, Chile. Electronic address: luiscea@med.uchile.cl.
authors.forename: Luis A
authors.initials: LA
authors.lastname: Cea
authors.affiliation: Departamento de Fisiología, Facultad de Ciencias Biológicas, Pontificia Universidad Católica de Chile, Santiago, Chile; Departamento Medicina Intensiva, Facultad de Medicina, Pontificia Universidad Católica de Chile, Santiago, Chile.
authors.forename: Elisa
authors.initials: E
authors.lastname: Balboa
authors.affiliation: Departamento de Fisiología, Facultad de Ciencias Biológicas, Pontificia Universidad Católica de Chile, Santiago, Chile; Centro Interdisciplinario de Neurociencias de Valparaíso, Valparaíso, Chile.
authors.forename: Carlos
authors.initials: C
authors.lastname: Puebla
authors.affiliation: Departamento de Fisiología, Facultad de Ciencias Biológicas, Pontificia Universidad Católica de Chile, Santiago, Chile; Centro Interdisciplinario de Neurociencias de Valparaíso, Valparaíso, Chile.
authors.forename: Aníbal A
authors.initials: AA
authors.lastname: Vargas
authors.affiliation: Departamento de Fisiología, Facultad de Ciencias Biológicas, Pontificia Universidad Católica de Chile, Santiago, Chile; Centro Interdisciplinario de Neurociencias de Valparaíso, Valparaíso, Chile.
authors.forename: Bruno A
authors.initials: BA
authors.lastname: Cisterna
authors.affiliation: Departamento de Fisiología, Facultad de Ciencias Biológicas, Pontificia Universidad Católica de Chile, Santiago, Chile; Centro Interdisciplinario de Neurociencias de Valparaíso, Valparaíso, Chile.
authors.forename: Rosalba
authors.initials: R
authors.lastname: Escamilla
authors.affiliation: Departamento Medicina Intensiva, Facultad de Medicina, Pontificia Universidad Católica de Chile, Santiago, Chile.
authors.forename: Tomás
authors.initials: T
authors.lastname: Regueira
authors.affiliation: Departamento de Fisiología, Facultad de Ciencias Biológicas, Pontificia Universidad Católica de Chile, Santiago, Chile; Centro Interdisciplinario de Neurociencias de Valparaíso, Valparaíso, Chile. Electronic address: jsaez@bio.puc.cl.
authors.forename: Juan C
authors.initials: JC
authors.lastname: Sáez
mesh_terms: D000818:Animals; D017630:Connexins / Q000096:biosynthesis* / Q000235:genetics; D003907:Dexamethasone / Q000009:adverse effects* / Q000494:pharmacology; D017629:Gap Junctions / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D005786:Gene Expression Regulation / Q000187:drug effects*; D051379:Mice; D008822:Mice, Transgenic; D009133:Muscular Atrophy / Q000139:chemically induced / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D009210:Myofibrils / Q000235:genetics / Q000378:metabolism* / Q000473:pathology
chemical_list: D017630:Connexins; D003907:Dexamethasone
keywords: Connexons; Ethidium bromide; Glucocorticoids; Membrane leakage; Purinergic receptors