Nifedipine Treatment Improves Muscle Function in Mdx Mice

Abstract

Duchenne muscular dystrophy (DMD) is a common genetic disorder characterized by chronic inflammation and severe muscle wasting caused by the absence of dystrophin. In mdx muscle fibers, we have shown that basal ATP release was increased and that extracellular ATP stimulation is pro-apoptotic. In normal fibers, ATP release is blocked by nifedipine leading us to study the potential therapeutic effect of nifedipine in mdx mice and its relation with extracellular ATP signaling. Six-week-old mdx mice were treated with daily intraperitoneal injections of nifedipine, 1mg/Kg for 1-week. This treatment significantly reduced extracellular ATP levels in adult mdx flexor digitorum brevis (FDB) fibers and lowered the intracellular resting Ca2+ concentration ([Ca2+]r) measured in vivo in the vastus lateralis. Acute treatment of mdx FDB fibers with apyrase, reduced [Ca2+]r to a similar extent as was seen in vastus lateralis after nifedipine treatment. Physiologically, nifedipine treatment increased muscle strength assessed by both the inverted grip-hanging test and forced swimming test, and decreased serum CK in mdx mice. Exploring mechanisms, nifedipine treatment reduced mRNA levels of iNOS, gp91phox, p47phox and Bax in mdx diaphragm muscles. We hypothesize that nifedipine, reduces basal ATP release thereby decreasing purinergic receptor activation, which in turn reduces [Ca2+]r and muscle destruction in mdx skeletal muscles. Funding: FONDECYT 1110467, Proyecto Anillo ACT1111 and AFM14562 (EJ, MC), NIH AR43140, AR052534 (PDA), U-INICIA VID 2011, U-INICIA 02/12M (MC).