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Biochim Biophys Acta Mol Basis Dis. 2019 Oct 1;1865(10):2765-2773. doi: 10.1016/j.bbadis.2019.06.014. Epub 2019 Jun 20.

De novo expression of functional connexins 43 and 45 hemichannels increases sarcolemmal permeability of skeletal myofibers during endotoxemia.

Author information

1
Instituto de Ciencias Biomédicas, Facultad de Ciencias de la Salud, Universidad Autónoma de Chile, Santiago, Chile. Electronic address: luis.cea@uautonoma.cl.
2
Departamento de Fisiología, Pontificia Universidad Católica de Chile, Santiago, Chile.
3
Departamento de Fisiología, Pontificia Universidad Católica de Chile, Santiago, Chile; Instituto de Neurociencias, Centro Interdisciplinario de Neurociencias de Valparaíso, Universidad de Valparaíso, Valparaíso, Chile; Instituto de Ciencias de la Salud, Universidad de O'Higgins, Rancagua, Chile.
4
Instituto de Ciencias Biomédicas, Facultad de Ciencias de la Salud, Universidad Autónoma de Chile, Santiago, Chile.
5
Consorcio de Investigación Naturalis SA, Santiago, Chile.
6
Departamento de Fisiología, Pontificia Universidad Católica de Chile, Santiago, Chile; Instituto de Neurociencias, Centro Interdisciplinario de Neurociencias de Valparaíso, Universidad de Valparaíso, Valparaíso, Chile; Instituto de Ingeniería Biológica y Médica, Pontificia Universidad Católica de Chile.
7
Centro de Pacientes Críticos, Clínica las Condes, Santiago, Chile.
8
Departamento de Fisiología, Pontificia Universidad Católica de Chile, Santiago, Chile; Instituto de Neurociencias, Centro Interdisciplinario de Neurociencias de Valparaíso, Universidad de Valparaíso, Valparaíso, Chile. Electronic address: jsaez@bio.puc.cl.

Abstract

Endotoxemia caused by bacterial lipopolysaccharides (LPSs) leads to severe skeletal muscular deterioration, starting with higher membrane permeability and decline in resting membrane potential (RMP). However, the molecular mechanism of such changes remains unclear. Here, we evaluated the possible involvement of connexin43- and connexin45-based hemichannels (Cx43 and Cx45 HCs, respectively) as putative mediators of sarcolemmal dysfunctions induced by LPS in control (Cx43fl/flCx45fl/fl) and Cx43/Cx45 expression-deficient (Cx43fl/flCx45fl/fl:Myo-Cre) skeletal mice myofibers. At 5 h of endotoxemia, control myofibers presented Cx43 and Cx45 proteins forming functional HCs. Additionally, myofibers from endotoxic control mice showed dye uptake in vivo, which was inhibited by carbenoxolone, a Cx HC blocker. A similar increase in membrane permeability was observed in myofibers freshly isolated from skeletal muscle of mice treated for 5 h with LPS, which was blocked by the Cx HC blocker and was absent in myofibers from mice simultaneously treated with LPS and boldine, which is a Cx HC blocker. The increase in sarcolemmal permeability was mimicked by isolated myofibers treated with pro-inflammatory cytokines (TNF-α and IL-1β) and occurred at 5 h after treatment. Endotoxemia also induced a significant increase in basal intracellular Ca2+ signal and a drop in RMP in control myofibers. These two changes were not elicited by myofibers deficient in Cx43/Cx45 expression. Therefore, sarcolemmal dysfunction characterizing endotoxemia is largely explained by the expression of functional Cx43 and Cx45 HCs. Hence, current therapy options for individuals suffering from endotoxic shock could be greatly improved with selective Cx HC inhibitors avoiding the underlying skeletal muscle dysfunction.

KEYWORDS:

Connexons; LPS; Membrane permeability; Pro-inflammatory cytokines; Resting membrane potential

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