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

Cea, Luis A.; Balboa, Elisa; Vargas, Anibal A.; Puebla, Carlos; Branes, Maria C.; Escamilla, Rosalba; Regueira, Tomas; Saez, Juan C

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 (Cx43(fl/fl) Cx45(fl/fl)) and Cx43/Cx45 expression-deficient (Cx43(fl/fl)Cx45(fl/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-alpha and IL-1 beta) and occurred at 5h 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.

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Título según WOS: De novo expression of functional connexins 43 and 45 hemichannels increases sarcolemmal permeability of skeletal myofibers during endotoxemia
Título según SCOPUS: De novo expression of functional connexins 43 and 45 hemichannels increases sarcolemmal permeability of skeletal myofibers during endotoxemia
Título de la Revista: BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR BASIS OF DISEASE
Volumen: 1865
Número: 10
Editorial: Elsevier
Fecha de publicación: 2019
Página de inicio: 2765
Página final: 2773
Idioma: English
DOI:

10.1016/j.bbadis.2019.06.014

Notas: ISI, SCOPUS