ATP release is altered in a mouse model for Duchenne muscular dystrophy and signals for proteins that promote cell death

Abstract

Several reports have described changes in ATP signaling in models for muscular dystrophy; nevertheless, none of them has been directly related with the dystrophy pathology. To study this pathway we used muscle fibers from flexor digitorum brevis isolated from normal and mdx mice. ATP was measured using luciferase, protein expression by Western blots and mRNA by qPCR. The basal ATP release occurs in bursts peaking every 5 minutes in fibers from both mice, being several fold more important in mdx fibers. We also studied the expression of different components of this pathway in isolated triads. We found that P2Y2 receptor and pannexin‐1 are increased and P2Y1 receptor is decreased in mdx fibers. Moreover, ‘selective’ dye uptake suggests that the activity of pannexin channels is elevated in dystrophic fibers. Upon stimulation with extracellular ATP, we found that a number of genes are differentially expressed between normal and dystrophic fibers. Among these genes, over expression of proapoptotic genes as Bax, Bim and PUMA in mdx fibers contrast to the repression of the same genes seen in normal fibers. This study suggests that ATP signaling is altered in mdx fibers and this pathway appears to be involved in the activation of a mechanism related with muscle cell death in muscular dystrophy.FONDAP‐15010006, AFM‐14562, FONDECYT‐1110467, CONICYT‐PhD fellowship (DV)

P2 Receptor Signaling in Motor Units in Muscular Dystrophy

“…ATP sensitivity has been reported to be much higher in mdx mice [ 89 ]. It has been shown that the release of ATP is greater in mdx mice, while the expression of P2Y 2 receptors is increased, and the expression of P2Y 1 receptors is reduced [ 90 ]. It was also found that suramin, which leads to the normal expression of P2Y 2 receptors, improved the clinical picture of Duchenne dystrophy [ 91 ].…”