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

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dc.cclicenceCC-BY-NCen
dc.contributor.authorYoung, Christopher N. J.en
dc.contributor.authorBrutkowski, W.en
dc.contributor.authorArkle, Stephenen
dc.contributor.authorLochmuller, H.en
dc.contributor.authorZablocki, K.en
dc.contributor.authorGorecki, Dariuszen
dc.contributor.authorLien, C-F.en
dc.date.acceptance2011-07-14en
dc.date.accessioned2017-12-20T08:55:26Z
dc.date.available2017-12-20T08:55:26Z
dc.date.issued2012-04-25
dc.descriptionOpen Accessen
dc.description.abstractDuchenne 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.en
dc.funderThis work was supported by the Interreg IV (AdMiN) grant to DCG, the Institute of Biomedical and Biomolecular Sciences PhD grant to C.Y. and the Medical Research Council UK through the Centre for Neuromuscular Diseases (G0601943) to H.L.en
dc.identifier.citationYoung, C.N.J et al. (2012) P2X7 purinoceptor alterations in dystrophic mdx mouse muscles: Relationship to pathology and potential target for treatment. Journal of Cellular and Molecular Medicine,16(5), pp.1026-1037en
dc.identifier.doihttps://doi.org/10.1111/j.1582-4934.2011.01397.x
dc.identifier.urihttp://hdl.handle.net/2086/15030
dc.language.isoenen
dc.peerreviewedYesen
dc.projectidN/Aen
dc.publisherBlackwell Publishingen
dc.researchinstituteLeicester Institute for Pharmaceutical Innovation - From Molecules to Practice (LIPI)en
dc.subjectP2X7en
dc.subjectDuchenne muscular dystrophyen
dc.subjectmdxen
dc.subjectCa2 influxen
dc.subjectERK signallingen
dc.subjectpurinoceptoren
dc.titleP2X7 purinoceptor alterations in dystrophic mdx mouse muscles: Relationship to pathology and potential target for treatment.en
dc.typeArticleen

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