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

Luis A. Cea, Carlos Puebla, Bruno A. Cisterna, Rosalba Escamilla, Aníbal A. Vargas, Marina Frank, Paloma Martínez-Montero, Carmen Prior, Jesús Molano, Isabel Esteban-Rodríguez, Ignacio Pascual, Pía Gallano, Gustavo Lorenzo, Héctor Pian, Luis C. Barrio, Klaus Willecke, Juan C. Sáez

Resultado de la investigación: Contribución a una revistaArtículo

23 Citas (Scopus)

Resumen

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 Cx43fl/flCx45fl/fl:Myo-Cre mice (deficient in skeletal muscle Cx43/Cx45 expression). These myofibers did not show elevated basal intracellular free Ca2+ 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 Cx43fl/flCx45fl/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 Cx43fl/flCx45fl/fl:Myo-Cre mice was significantly better than that of control mdx Cx43fl/flCx45fl/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.

Idioma originalInglés
Páginas (desde-hasta)2583-2599
Número de páginas17
PublicaciónCellular and Molecular Life Sciences
Volumen73
N.º13
DOI
EstadoPublicada - 1 jul 2016

Áreas temáticas de ASJC Scopus

  • Medicina molecular
  • Biología molecular
  • Farmacología
  • Neurociencia celular y molecular
  • Biología celular

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    Cea, L. A., Puebla, C., Cisterna, B. A., Escamilla, R., Vargas, A. A., Frank, M., Martínez-Montero, P., Prior, C., Molano, J., Esteban-Rodríguez, I., Pascual, I., Gallano, P., Lorenzo, G., Pian, H., Barrio, L. C., Willecke, K., & Sáez, J. C. (2016). Fast skeletal myofibers of mdx mouse, model of Duchenne muscular dystrophy, express connexin hemichannels that lead to apoptosis. Cellular and Molecular Life Sciences, 73(13), 2583-2599. https://doi.org/10.1007/s00018-016-2132-2