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Duchenne 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 [Ca 2+ ] 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 [Ca 2+ ] 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 [Ca 2+ ] 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 gp91 phox /p47 phox  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 [Ca 2+ ] r  in  mdx  skeletal muscle cells. The results in this work open new perspectives towards possible targets for pharmacological approaches to treat DMD.

plos one

Nifedipine Treatment Reduces Resting Calcium Concentration, Oxidative and Apoptotic Gene Expression, and Improves Muscle Function in Dystrophic mdx Mice