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Increased susceptibility to ATP via alteration of P2X receptor function in dystrophic mdx mouse muscle cells

Davy Yeung^*,1, Krzysztof Zabocki, Chun-Fu Lien^*, Taiwen Jiang^*, Stephen Arkle^*, Wojciech Brutkowski, James Brown^*, Hanns Lochmuller, Joseph Simon, Eric A. Barnard and Dariusz C. Górecki^*,2

^* Institute of Biomedical and Biomolecular Sciences, School of Pharmacy and Biomedical Sciences, Portsmouth, UK;
Nencki Institute of Experimental Biology, Warsaw, Poland;
Friedrich-Baur Institute, Department of Neurology, Ludwig-Maximilians University, München, Germany; and
Department of Pharmacology, University of Cambridge, Cambridge, UK

²Correspondence: Institute of Biomedical and Biomolecular Sciences, St. Michael’s Building, White Swan Road, Portsmouth, PO1 2DT, UK. E-mail: darek.gorecki{at}port.ac.uk

Pathological cellular hallmarks of Duchenne muscular dystrophy (DMD) include, among others, abnormal calcium homeostasis. Changes in the expression of specific receptors for extracellular ATP in dystrophic muscle have been recently documented: here, we demonstrate that at the earliest, myoblast stage of developing dystrophic muscle a purinergic dystrophic phenotype arises. In myoblasts of a dystrophin-negative muscle cell line established from the mdx mouse model of DMD but not in normal myoblasts, exposure to extracellular ATP triggered a strong increase in cytoplasmic Ca²⁺ concentrations. Influx of extracellular Ca²⁺ was stimulated by ATP and BzATP and inhibited by zinc, Coomassie Brilliant Blue-G, and KN-62, demonstrating activation of P2X7 receptors. Significant expression of P2X4 and P2X7 proteins was immunodetected in dystrophic myoblasts. Therefore, full-length dystrophin appears, surprisingly, to play an important role in myoblasts in controlling responses to ATP. Our results suggest that altered function of P2X receptors may be an important contributor to pathogenic Ca²⁺ entry in dystrophic mouse muscle and may have implications for the pathogenesis of muscular dystrophies. Treatments aiming at inhibition of specific ATP receptors could be of a potential therapeutic benefit.—Yeung, D., Zabocki, K., Lien, C.-F., Jiang, T., Arkle, S., Brutkowski, W., Brown, J., Lochmuller, H., Simon, J., Barnard, E. A., Górecki, D. C. Increased susceptibility to ATP via alteration of P2X receptor function in dystrophic mdx mouse muscle cells.

Key Words: Duchenne muscular dystrophy • ATP • P2X receptor • myoblast • mdx mouse

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