Dexamethasone-induced muscular atrophy is mediated by functional expression of connexin-based hemichannels

Luis A. Cea, Elisa Balboa, Carlos Puebla, Aníbal A. Vargas, Bruno A. Cisterna, Rosalba Escamilla, Tomás Regueira, Juan C. Sáez

Research output: Contribution to journalArticlepeer-review

36 Citations (Scopus)

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 (Cx43fl/flCx45fl/fl) and Cx43/Cx45 expression-deficient (Cx43fl/flCx45fl/fl:Myo-Cre) skeletal myofibers. Myofibers of Cx43fl/flCx45fl/fl mice treated with DEX (5 h) expressed several proteins that form non-selective membrane channels (Cx39, Cx43, Cx45, Panx1, P2X7 receptor and TRPV2). After 5 h DEX treatment in vivo, myofibers of Cx43fl/flCx45fl/fl mice showed Evans blue uptake, which was absent in myofibers of Cx43fl/flCx45fl/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 Ca2 + signal and a reduction in resting membrane potential in Cx43fl/flCx45fl/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 (7 days) increased atrogin-1 and Murf-1 and reduced the cross sectional area of Cx43fl/flCx45fl/fl myofibers, but these parameters remained unaffected in Cx43fl/flCx45fl/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.

Original languageEnglish
Pages (from-to)1891-1899
Number of pages9
JournalBiochimica et Biophysica Acta - Molecular Basis of Disease
Volume1862
Issue number10
DOIs
Publication statusPublished - 1 Oct 2016

Keywords

  • Connexons
  • Ethidium bromide
  • Glucocorticoids
  • Membrane leakage
  • Purinergic receptors

ASJC Scopus subject areas

  • Molecular Medicine
  • Molecular Biology

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