Artículos de revistas
Electrical Stimuli Are Anti-Apoptotic in Skeletal Muscle via Extracellular ATP. Alteration of This Signal in Mdx Mice Is a Likely Cause of Dystrophy
Fecha
2013-11Registro en:
PLoS ONE 8(11): e75340
doi:10.1371/journal.pone.0075340
Autor
Valladares, Denisse
Almarza, Gonzalo
Contreras, Ariel
Pavez, Mario
Buvinic Radic, Sonja
Jaimovich Pérez, Enrique
Casas Atala, Mariana
Institución
Resumen
ATP signaling has been shown to regulate gene expression in skeletal muscle and to be altered in models of muscular
dystrophy. We have previously shown that in normal muscle fibers, ATP released through Pannexin1 (Panx1) channels after
electrical stimulation plays a role in activating some signaling pathways related to gene expression. We searched for a
possible role of ATP signaling in the dystrophy phenotype. We used muscle fibers from flexor digitorum brevis isolated from
normal and mdx mice. We demonstrated that low frequency electrical stimulation has an anti-apoptotic effect in normal
muscle fibers repressing the expression of Bax, Bim and PUMA. Addition of exogenous ATP to the medium has a similar
effect. In dystrophic fibers, the basal levels of extracellular ATP were higher compared to normal fibers, but unlike control
fibers, they do not present any ATP release after low frequency electrical stimulation, suggesting an uncoupling between
electrical stimulation and ATP release in this condition. Elevated levels of Panx1 and decreased levels of Cav1.1
(dihydropyridine receptors) were found in triads fractions prepared from mdx muscles. Moreover, decreased
immunoprecipitation of Cav1.1 and Panx1, suggest uncoupling of the signaling machinery. Importantly, in dystrophic
fibers, exogenous ATP was pro-apoptotic, inducing the transcription of Bax, Bim and PUMA and increasing the levels of
activated Bax and cytosolic cytochrome c. These evidence points to an involvement of the ATP pathway in the activation of
mechanisms related with cell death in muscular dystrophy, opening new perspectives towards possible targets for
pharmacological therapies.