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: Article

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

Huella dactilar

Inbred mdx Mouse
Connexins
Duchenne Muscular Dystrophy
Skeletal Muscle
Apoptosis
Connexin 43
Muscles
Sarcolemma
Dystrophin
Muscular Dystrophies
Annexin A5
Creatine Kinase
Caspase 3
Permeability
Necrosis
Macrophages
Inflammation
Biopsy

ASJC Scopus subject areas

  • Molecular Medicine
  • Molecular Biology
  • Pharmacology
  • Cellular and Molecular Neuroscience
  • Cell Biology

Citar esto

Cea, Luis A. ; Puebla, Carlos ; Cisterna, Bruno A. ; Escamilla, Rosalba ; Vargas, Aníbal A. ; Frank, Marina ; Martínez-Montero, Paloma ; Prior, Carmen ; Molano, Jesús ; Esteban-Rodríguez, Isabel ; Pascual, Ignacio ; Gallano, Pía ; Lorenzo, Gustavo ; Pian, Héctor ; Barrio, Luis C. ; Willecke, Klaus ; Sáez, Juan C. / Fast skeletal myofibers of mdx mouse, model of Duchenne muscular dystrophy, express connexin hemichannels that lead to apoptosis. En: Cellular and Molecular Life Sciences. 2016 ; Vol. 73, N.º 13. pp. 2583-2599.
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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 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.",
keywords = "Cell death, Connexons, Evans blue uptake, NF-κB, P2X receptors, Pannexin1",
author = "Cea, {Luis A.} and Carlos Puebla and Cisterna, {Bruno A.} and Rosalba Escamilla and Vargas, {An{\'i}bal A.} and Marina Frank and Paloma Mart{\'i}nez-Montero and Carmen Prior and Jes{\'u}s Molano and Isabel Esteban-Rodr{\'i}guez and Ignacio Pascual and P{\'i}a Gallano and Gustavo Lorenzo and H{\'e}ctor Pian and Barrio, {Luis C.} and Klaus Willecke and S{\'a}ez, {Juan C.}",
year = "2016",
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doi = "10.1007/s00018-016-2132-2",
language = "English",
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Cea, LA, Puebla, C, Cisterna, BA, Escamilla, R, Vargas, AA, Frank, M, Martínez-Montero, P, Prior, C, Molano, J, Esteban-Rodríguez, I, Pascual, I, Gallano, P, Lorenzo, G, Pian, H, Barrio, LC, Willecke, K & Sáez, JC 2016, 'Fast skeletal myofibers of mdx mouse, model of Duchenne muscular dystrophy, express connexin hemichannels that lead to apoptosis', Cellular and Molecular Life Sciences, vol. 73, n.º 13, pp. 2583-2599. https://doi.org/10.1007/s00018-016-2132-2

Fast skeletal myofibers of mdx mouse, model of Duchenne muscular dystrophy, express connexin hemichannels that lead to apoptosis. / Cea, Luis A.; Puebla, Carlos; Cisterna, Bruno A.; Escamilla, Rosalba; Vargas, Aníbal A.; Frank, Marina; Martínez-Montero, Paloma; Prior, Carmen; Molano, Jesús; Esteban-Rodríguez, Isabel; Pascual, Ignacio; Gallano, Pía; Lorenzo, Gustavo; Pian, Héctor; Barrio, Luis C.; Willecke, Klaus; Sáez, Juan C.

En: Cellular and Molecular Life Sciences, Vol. 73, N.º 13, 01.07.2016, p. 2583-2599.

Resultado de la investigación: Article

TY - JOUR

T1 - Fast skeletal myofibers of mdx mouse, model of Duchenne muscular dystrophy, express connexin hemichannels that lead to apoptosis

AU - Cea, Luis A.

AU - Puebla, Carlos

AU - Cisterna, Bruno A.

AU - Escamilla, Rosalba

AU - Vargas, Aníbal A.

AU - Frank, Marina

AU - Martínez-Montero, Paloma

AU - Prior, Carmen

AU - Molano, Jesús

AU - Esteban-Rodríguez, Isabel

AU - Pascual, Ignacio

AU - Gallano, Pía

AU - Lorenzo, Gustavo

AU - Pian, Héctor

AU - Barrio, Luis C.

AU - Willecke, Klaus

AU - Sáez, Juan C.

PY - 2016/7/1

Y1 - 2016/7/1

N2 - 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.

AB - 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.

KW - Cell death

KW - Connexons

KW - Evans blue uptake

KW - NF-κB

KW - P2X receptors

KW - Pannexin1

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U2 - 10.1007/s00018-016-2132-2

DO - 10.1007/s00018-016-2132-2

M3 - Article

C2 - 26803842

AN - SCOPUS:84955323343

VL - 73

SP - 2583

EP - 2599

JO - Cellular and Molecular Life Sciences

JF - Cellular and Molecular Life Sciences

SN - 1420-682X

IS - 13

ER -