P2X7 purinoceptor alterations in dystrophic mdx mouse muscles: relationship to pathology and potential target for treatment

Journal of Cellular and Molecular Medicine

Christopher N. J. Young²  Wojciech Brutkowski²  Chun-Fu Lien²  Stephen Arkle²  Hanns Lochmüller³  Krzysztof Zabłocki¹ 

[1] Nencki Institute of Experimental Biology, Warsaw, Poland;School of Pharmacy and Biomedical Sciences, University of Portsmouth, Portsmouth, UK;Institute of Human Genetics, Newcastle University, Newcastle, UK

关键词: P2X7;    Duchenne muscular dystrophy;    mdx;    Ca2+ influx;    ERK signalling;    purinoceptor;   

DOI  :  10.1111/j.1582-4934.2011.01397.x

来源: Wiley

【 摘 要 】

Abstract

Duchenne muscular dystrophy (DMD) is a lethal inherited muscle disorder. Pathological characteristics of DMD skeletal muscles include, among others, abnormal Ca²⁺ homeostasis and cell signalling. Here, in the mdx mouse model of DMD, we demonstrate significant P2X7 receptor abnormalities in isolated primary muscle cells and cell lines and in dystrophic muscles in vivo. P2X7 mRNA expression in dystrophic muscles was significantly up-regulated but without alterations of specific splice variant patterns. P2X7 protein was also up-regulated and this was associated with altered function of P2X7 receptors producing increased responsiveness of cytoplasmic Ca²⁺ and extracellular signal-regulated kinase (ERK) phosphorylation to purinergic stimulation and altered sensitivity to NAD. Ca²⁺ influx and ERK signalling were stimulated by ATP and BzATP, inhibited by specific P2X7 antagonists and insensitive to ivermectin, confirming P2X7 receptor involvement. Despite the presence of pannexin-1, prolonged P2X7 activation did not trigger cell permeabilization to propidium iodide or Lucifer yellow. In dystrophic mice, in vivo treatment with the P2X7 antagonist Coomassie Brilliant Blue reduced the number of degeneration–regeneration cycles in mdx skeletal muscles. Altered P2X7 expression and function is thus an important feature in dystrophic mdx muscle and treatments aiming to inhibit P2X7 receptor might slow the progression of this disease.

【 授权许可】

Unknown   
© 2011 The Authors Journal of Cellular and Molecular Medicine © 2011 Foundation for Cellular and Molecular Medicine/Blackwell Publishing Ltd