title: Fast skeletal myofibers of mdx mouse, model of Duchenne muscular dystrophy, express connexin hemichannels that lead to apoptosis.
abstract: Skeletal muscles of patients with Duchenne muscular dystrophy (DMD) show numerous alterations including inflammation, apoptosis, and necrosis of myofibers. However, the molecular mechanism that explains these changes remains largely unknown. Here, the involvement of hemichannels formed by connexins (Cx HCs) was evaluated in skeletal muscle of mdx mouse model of DMD. Fast myofibers of mdx mice were found to express three connexins (39, 43 and 45) and high sarcolemma permeability, which was absent in myofibers of mdx Cx43(fl/fl)Cx45(fl/fl):Myo-Cre mice (deficient in skeletal muscle Cx43/Cx45 expression). These myofibers did not show elevated basal intracellular free Ca(2+) levels, immunoreactivity to phosphorylated p65 (active NF-κB), eNOS and annexin V/active Caspase 3 (marker of apoptosis) but presented dystrophin immunoreactivity. Moreover, muscles of mdx Cx43(fl/fl)Cx45(fl/fl):Myo-Cre mice exhibited partial decrease of necrotic features (big cells and high creatine kinase levels). Accordingly, these muscles showed similar macrophage infiltration as control mdx muscles. Nonetheless, the hanging test performance of mdx Cx43(fl/fl)Cx45(fl/fl):Myo-Cre mice was significantly better than that of control mdx Cx43(fl/fl)Cx45(fl/fl) mice. All three Cxs found in skeletal muscles of mdx mice were also detected in fast myofibers of biopsy specimens from patients with muscular dystrophy. Thus, reduction of Cx expression and/or function of Cx HCs may be potential therapeutic approaches to abrogate myofiber apoptosis in DMD.
authors.affiliation: Present: Program of Anatomy and Developmental Biology, Institute of Biomedical Sciences, Faculty of Medicine, University of Chile, Santiago, Chile. luiscea@med.uchile.cl.|Departamento de Fisiología, Pontificia Universidad Católica de Chile, Av. Libertador Bernardo O'Higgins 340, Santiago, Chile. luiscea@med.uchile.cl.
authors.forename: Luis A
authors.initials: LA
authors.lastname: Cea
authors.affiliation: Departamento de Fisiología, Pontificia Universidad Católica de Chile, Av. Libertador Bernardo O'Higgins 340, Santiago, Chile.|Centro Interdisciplinario de Neurociencias de Valparaíso, Valparaíso, Chile.
authors.forename: Carlos
authors.initials: C
authors.lastname: Puebla
authors.affiliation: Departamento de Fisiología, Pontificia Universidad Católica de Chile, Av. Libertador Bernardo O'Higgins 340, Santiago, Chile.|Centro Interdisciplinario de Neurociencias de Valparaíso, Valparaíso, Chile.
authors.forename: Bruno A
authors.initials: BA
authors.lastname: Cisterna
authors.affiliation: Departamento de Fisiología, Pontificia Universidad Católica de Chile, Av. Libertador Bernardo O'Higgins 340, Santiago, Chile.|Centro Interdisciplinario de Neurociencias de Valparaíso, Valparaíso, Chile.
authors.forename: Rosalba
authors.initials: R
authors.lastname: Escamilla
authors.affiliation: Departamento de Fisiología, Pontificia Universidad Católica de Chile, Av. Libertador Bernardo O'Higgins 340, Santiago, Chile.
authors.forename: Aníbal A
authors.initials: AA
authors.lastname: Vargas
authors.affiliation: Division of Molecular Genetics, Life and Medical Sciences Institute, University of Bonn, 53115, Bonn, Germany.
authors.forename: Marina
authors.initials: M
authors.lastname: Frank
authors.affiliation: Unidad de Genética Molecular-INGEMM, Hospital Universitario La Paz-IdIPAZ, Madrid, Spain.
authors.forename: Paloma
authors.initials: P
authors.lastname: Martínez-Montero
authors.affiliation: Unidad de Genética Molecular-INGEMM, Hospital Universitario La Paz-IdIPAZ, Madrid, Spain.
authors.forename: Carmen
authors.initials: C
authors.lastname: Prior
authors.affiliation: Unidad de Genética Molecular-INGEMM, Hospital Universitario La Paz-IdIPAZ, Madrid, Spain.
authors.forename: Jesús
authors.initials: J
authors.lastname: Molano
authors.affiliation: Servicio de Anatomía Patológica, Hospital Universitario La Paz-IdIPAZ, Madrid, Spain.
authors.forename: Isabel
authors.initials: I
authors.lastname: Esteban-Rodríguez
authors.affiliation: Servicio de Neuropediatría, Hospital Universitario La Paz-IdIPAZ, Madrid, Spain.
authors.forename: Ignacio
authors.initials: I
authors.lastname: Pascual
authors.affiliation: Servicio de Genética, Hospital Santa Creu i Sant Pablo-CIBERER, Barcelona, Spain.
authors.forename: Pía
authors.initials: P
authors.lastname: Gallano
authors.affiliation: Servicio de Pediatria, "Ramón y Cajal" Hospital-IRYCIS, Madrid, Spain.
authors.forename: Gustavo
authors.initials: G
authors.lastname: Lorenzo
authors.affiliation: Servicio de Anatomía Patológica, "Ramón y Cajal" Hospital-IRYCIS, Madrid, Spain.
authors.forename: Héctor
authors.initials: H
authors.lastname: Pian
authors.affiliation: Unidad de Neurología Experimental, "Ramón y Cajal" Hospital-IRYCIS, Madrid, Spain.
authors.forename: Luis C
authors.initials: LC
authors.lastname: Barrio
authors.affiliation: Division of Molecular Genetics, Life and Medical Sciences Institute, University of Bonn, 53115, Bonn, Germany.
authors.forename: Klaus
authors.initials: K
authors.lastname: Willecke
authors.affiliation: Departamento de Fisiología, Pontificia Universidad Católica de Chile, Av. Libertador Bernardo O'Higgins 340, Santiago, Chile. jsaez@bio.puc.cl.|Centro Interdisciplinario de Neurociencias de Valparaíso, Valparaíso, Chile. jsaez@bio.puc.cl.
authors.forename: Juan C
authors.initials: JC
authors.lastname: Sáez
mesh_terms: D000818:Animals; D017209:Apoptosis; D016923:Cell Death; D017630:Connexins / Q000032:analysis* / Q000378:metabolism; D016189:Dystrophin / Q000032:analysis / Q000378:metabolism; D005260:Female; D006801:Humans; D008297:Male; D018101:Mice, Inbred mdx; D018485:Muscle Fibers, Skeletal / Q000378:metabolism / Q000473:pathology; D018482:Muscle, Skeletal / Q000378:metabolism / Q000473:pathology*; D020388:Muscular Dystrophy, Duchenne / Q000378:metabolism / Q000473:pathology*; D016328:NF-kappa B / Q000032:analysis / Q000378:metabolism; D058486:Receptors, Purinergic P2X7 / Q000032:analysis / Q000378:metabolism
chemical_list: D017630:Connexins; D016189:Dystrophin; D016328:NF-kappa B; D058486:Receptors, Purinergic P2X7
keywords: Cell death; Connexons; Evans blue uptake; NF-κB; P2X7 receptors; Pannexin1