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dc.contributor.authorAltamirano, Franciscoen_US
dc.contributor.authorValladares, Denisseen_US
dc.contributor.authorHenríquez-Olguín, Carlosen_US
dc.contributor.authorCasas, Marianaen_US
dc.contributor.authorLópez, Jose R.en_US
dc.contributor.authorAllen, Paul D.en_US
dc.contributor.authorJaimovich, Enriqueen_US
dc.date.accessioned2014-03-11T10:17:06Z
dc.date.issued2013en_US
dc.identifier.citationAltamirano, Francisco, Denisse Valladares, Carlos Henríquez-Olguín, Mariana Casas, Jose R. López, Paul D. Allen, and Enrique Jaimovich. 2013. “Nifedipine Treatment Reduces Resting Calcium Concentration, Oxidative and Apoptotic Gene Expression, and Improves Muscle Function in Dystrophic mdx Mice.” PLoS ONE 8 (12): e81222. doi:10.1371/journal.pone.0081222. http://dx.doi.org/10.1371/journal.pone.0081222.en
dc.identifier.issn1932-6203en
dc.identifier.urihttp://nrs.harvard.edu/urn-3:HUL.InstRepos:11879342
dc.description.abstractDuchenne Muscular Dystrophy (DMD) is a recessive X-linked genetic disease, caused by mutations in the gene encoding dystrophin. DMD is characterized in humans and in mdx mice by a severe and progressive destruction of muscle fibers, inflammation, oxidative/nitrosative stress, and cell death. In mdx muscle fibers, we have shown that basal ATP release is increased and that extracellular ATP stimulation is pro-apoptotic. In normal fibers, depolarization-induced ATP release is blocked by nifedipine, leading us to study the potential therapeutic effect of nifedipine in mdx muscles and its relation with extracellular ATP signaling. Acute exposure to nifedipine (10 µM) decreased [Ca2+]r, NF-κB activity and iNOS expression in mdx myotubes. In addition, 6-week-old mdx mice were treated with daily intraperitoneal injections of nifedipine, 1 mg/Kg for 1 week. This treatment lowered the [Ca2+]r measured in vivo in the mdx vastus lateralis. We demonstrated that extracellular ATP levels were higher in adult mdx flexor digitorum brevis (FDB) fibers and can be significantly reduced after 1 week of treatment with nifedipine. Interestingly, acute treatment of mdx FDB fibers with apyrase, an enzyme that completely degrades extracellular ATP to AMP, reduced [Ca2+]r to a similar extent as was seen in FDB fibers after 1-week of nifedipine treatment. Moreover, we demonstrated that nifedipine treatment reduced mRNA levels of pro-oxidative/nitrosative (iNOS and gp91phox/p47phox NOX2 subunits) and pro-apoptotic (Bax) genes in mdx diaphragm muscles and lowered serum creatine kinase (CK) levels. In addition, nifedipine treatment increased muscle strength assessed by the inverted grip-hanging test and exercise tolerance measured with forced swimming test in mdx mice. We hypothesize that nifedipine reduces basal ATP release, thereby decreasing purinergic receptor activation, which in turn reduces [Ca2+]r in mdx skeletal muscle cells. The results in this work open new perspectives towards possible targets for pharmacological approaches to treat DMD.en
dc.language.isoen_USen
dc.publisherPublic Library of Scienceen
dc.relation.isversionofdoi:10.1371/journal.pone.0081222en
dc.relation.hasversionhttp://www.ncbi.nlm.nih.gov/pmc/articles/PMC3857175/pdf/en
dash.licenseLAAen_US
dc.titleNifedipine Treatment Reduces Resting Calcium Concentration, Oxidative and Apoptotic Gene Expression, and Improves Muscle Function in Dystrophic mdx Miceen
dc.typeJournal Articleen_US
dc.description.versionVersion of Recorden
dc.relation.journalPLoS ONEen
dash.depositing.authorAllen, Paul D.en_US
dc.date.available2014-03-11T10:17:06Z
dc.identifier.doi10.1371/journal.pone.0081222*
dash.contributor.affiliatedAllen, Paul


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