Journal
BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR BASIS OF DISEASE
Volume 1862, Issue 10, Pages 1891-1899Publisher
ELSEVIER
DOI: 10.1016/j.bbadis.2016.07.003
Keywords
Connexons; Membrane leakage; Ethidium bromide; Purinergic receptors; Glucocorticoids
Funding
- 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]
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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.
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