Fast skeletal myofibers of mdx mouse, model of Duchenne muscular dystrophy, express connexin hemichannels that lead to apoptosis
Por:
Cea, LA, Puebla, C, Cisterna, BA, Escamilla, R, Vargas, AA, Frank, M, Martinez-Montero, P, Prior, C, Molano, J, Esteban-Rodriguez, I, Pascual, I, Gallano, P, Lorenzo, G, Pian, H, Barrio, LC, Willecke, K, Saez, JC
Publicada:
1 jul 2016
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 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 Ca2+ levels, immunoreactivity to phosphorylated p65 (active NF-kappa B), 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.
Filiaciones:
Cea, LA:
Univ Chile, Inst Biomed Sci, Program Anat & Dev Biol, Fac Med, Santiago, Chile
Pontificia Univ Catolica Chile, Dept Fisiol, Ave Libertador Bernardo OHiggins 340, Santiago, Chile
Puebla, C:
Pontificia Univ Catolica Chile, Dept Fisiol, Ave Libertador Bernardo OHiggins 340, Santiago, Chile
Ctr Interdisciplinario Neurociencias Valparaiso, Valparaiso, Chile
Cisterna, BA:
Pontificia Univ Catolica Chile, Dept Fisiol, Ave Libertador Bernardo OHiggins 340, Santiago, Chile
Ctr Interdisciplinario Neurociencias Valparaiso, Valparaiso, Chile
Escamilla, R:
Pontificia Univ Catolica Chile, Dept Fisiol, Ave Libertador Bernardo OHiggins 340, Santiago, Chile
Ctr Interdisciplinario Neurociencias Valparaiso, Valparaiso, Chile
Vargas, AA:
Pontificia Univ Catolica Chile, Dept Fisiol, Ave Libertador Bernardo OHiggins 340, Santiago, Chile
Frank, M:
Univ Bonn, Life & Med Sci Inst, Div Mol Genet, D-53115 Bonn, Germany
Martinez-Montero, P:
Hosp Univ La Paz, Unidad Genet Mol INGEMM, IdIPAZ, Madrid, Spain
Prior, C:
Hosp Univ La Paz, Unidad Genet Mol INGEMM, IdIPAZ, Madrid, Spain
Molano, J:
Hosp Univ La Paz, Unidad Genet Mol INGEMM, IdIPAZ, Madrid, Spain
Esteban-Rodriguez, I:
Hosp Univ La Paz, Serv Anat Patol, IdIPAZ, Madrid, Spain
Pascual, I:
Hosp Univ La Paz, Serv Neuropediat, IdIPAZ, Madrid, Spain
Gallano, P:
Hosp Santa Creu & St Pablo, Serv Genet, CIBERER, Barcelona, Spain
Lorenzo, G:
Hosp Ramon & Cajal, Serv Pediat, IRYCIS, E-28034 Madrid, Spain
Pian, H:
Hosp Ramon & Cajal, Serv Anat Patol, IRYCIS, E-28034 Madrid, Spain
Barrio, LC:
Hosp Ramon & Cajal, Unidad Neurol Expt, IRYCIS, E-28034 Madrid, Spain
Willecke, K:
Univ Bonn, Life & Med Sci Inst, Div Mol Genet, D-53115 Bonn, Germany
Saez, JC:
Pontificia Univ Catolica Chile, Dept Fisiol, Ave Libertador Bernardo OHiggins 340, Santiago, Chile
Ctr Interdisciplinario Neurociencias Valparaiso, Valparaiso, Chile
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