Format

Send to

Choose Destination
Cell Mol Life Sci. 2016 Jul;73(13):2583-99. doi: 10.1007/s00018-016-2132-2. Epub 2016 Jan 23.

Fast skeletal myofibers of mdx mouse, model of Duchenne muscular dystrophy, express connexin hemichannels that lead to apoptosis.

Author information

1
Present: Program of Anatomy and Developmental Biology, Institute of Biomedical Sciences, Faculty of Medicine, University of Chile, Santiago, Chile. luiscea@med.uchile.cl.
2
Departamento de Fisiología, Pontificia Universidad Católica de Chile, Av. Libertador Bernardo O'Higgins 340, Santiago, Chile. luiscea@med.uchile.cl.
3
Departamento de Fisiología, Pontificia Universidad Católica de Chile, Av. Libertador Bernardo O'Higgins 340, Santiago, Chile.
4
Centro Interdisciplinario de Neurociencias de Valparaíso, Valparaíso, Chile.
5
Division of Molecular Genetics, Life and Medical Sciences Institute, University of Bonn, 53115, Bonn, Germany.
6
Unidad de Genética Molecular-INGEMM, Hospital Universitario La Paz-IdIPAZ, Madrid, Spain.
7
Servicio de Anatomía Patológica, Hospital Universitario La Paz-IdIPAZ, Madrid, Spain.
8
Servicio de Neuropediatría, Hospital Universitario La Paz-IdIPAZ, Madrid, Spain.
9
Servicio de Genética, Hospital Santa Creu i Sant Pablo-CIBERER, Barcelona, Spain.
10
Servicio de Pediatria, "Ramón y Cajal" Hospital-IRYCIS, Madrid, Spain.
11
Servicio de Anatomía Patológica, "Ramón y Cajal" Hospital-IRYCIS, Madrid, Spain.
12
Unidad de Neurología Experimental, "Ramón y Cajal" Hospital-IRYCIS, Madrid, Spain.
13
Departamento de Fisiología, Pontificia Universidad Católica de Chile, Av. Libertador Bernardo O'Higgins 340, Santiago, Chile. jsaez@bio.puc.cl.
14
Centro Interdisciplinario de Neurociencias de Valparaíso, Valparaíso, Chile. jsaez@bio.puc.cl.

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.

KEYWORDS:

Cell death; Connexons; Evans blue uptake; NF-κB; P2X7 receptors; Pannexin1

PMID:
26803842
DOI:
10.1007/s00018-016-2132-2
[Indexed for MEDLINE]

Supplemental Content

Full text links

Icon for Springer
Loading ...
Support Center