Dexamethasone-induced muscular atrophy is mediated by functional expression of connexin-based hemichannels
Author
dc.contributor.author
Cea Pisani, Luis
Author
dc.contributor.author
Balboa, Elisa
Author
dc.contributor.author
Puebla, Carlos
Author
dc.contributor.author
Vargas, Aníbal
Author
dc.contributor.author
Cisterna, Bruno
Author
dc.contributor.author
Escamilla, Rosalba
Author
dc.contributor.author
Regueira, Tomás
Author
dc.contributor.author
Sáez, Juan C.
Admission date
dc.date.accessioned
2016-12-28T13:32:39Z
Available date
dc.date.available
2016-12-28T13:32:39Z
Publication date
dc.date.issued
2016
Cita de ítem
dc.identifier.citation
Biochimica et Biophysica Acta 1862 (2016) 1891–1899
es_ES
Identifier
dc.identifier.other
10.1016/j.bbadis.2016.07.003
Identifier
dc.identifier.uri
https://repositorio.uchile.cl/handle/2250/142157
Abstract
dc.description.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 (5 h) expressed several proteins that form non-selective membrane channels (Cx39, Cx43, Cx45, Panxi, P2X7 receptor and TRPV2). After 5 h 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 P2X(7) receptor inhibitors. DEX also induced a significant increase in basal intracellular Ca2+ 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 NF kappa B activation and increased mRNA levels of TNF-alpha. in control but not in Cx43(fl/fl)Cx45(fl/fl) expression-deficient myofibers. Finally, a prolonged DEX treatment (7 days) 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. (C) 2016 Elsevier B.V. All rights reserved
es_ES
Patrocinador
dc.description.sponsorship
CONICYT/PAI Proyecto de Insertion en la Academia 79140023
Fondo Nacional de Desarrollo Cientifico y Tecnologico (FONDECYT) 1141092 1150291
FONDECYT Postdoctorado grant 3160594
Iniciativa Cientifica Milenio-Economia P09-022-F