Nifedipine treatment reduces resting calcium concentration, oxidative and apoptotic gene expression, and improves muscle function in dystrophic mdx mice.
Nifedipine treatment reduces resting calcium concentration, oxidative and apoptotic gene expression, and improves muscle function in dystrophic mdx mice.
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DOI：
10.1371/journal.pone.0081222
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发表时间：
2013
期刊：
影响因子：
3.7
通讯作者：
Jaimovich E
中科院分区：
文献类型：
--
作者：
Altamirano F;Valladares D;Henríquez-Olguín C;Casas M;López JR;Allen PD;Jaimovich E
杜氏肌营养不良症（DMD）是一种隐性x连锁遗传病，由编码肌营养不良蛋白的基因突变引起。DMD在人类和mdx小鼠中的特征是肌肉纤维的严重和进行性破坏、炎症、氧化/亚硝化应激和细胞死亡。在mdx肌纤维中，我们已经表明基础ATP释放增加，细胞外ATP刺激是促凋亡的。在正常纤维中，去极化诱导的ATP释放被硝苯地平阻断，这促使我们研究硝苯地平对mdx肌肉的潜在治疗作用及其与细胞外ATP信号传导的关系。急性暴露于硝苯地平（10µM）可降低mdx肌管[Ca2+]r、NF-κB活性和iNOS表达。此外，6周龄mdx小鼠每天腹腔注射硝苯地平，剂量为1 mg/Kg，连续1周。这种治疗降低了mdx股外侧肌体内测量的[Ca2+]r。我们证明了成人mdx指屈肌短（FDB）纤维的细胞外ATP水平较高，并在硝苯地平治疗1周后显着降低。有趣的是，用apyrase（一种完全将细胞外ATP降解为AMP的酶）急性治疗mdx FDB纤维，与硝苯地平治疗1周后FDB纤维中[Ca2+]r的降低程度相似。此外，我们证明硝苯地平治疗降低了mdx膈肌中促氧化/亚硝化（iNOS和gp91phox/p47phox NOX2亚基）和促凋亡（Bax）基因的mRNA水平，并降低了血清肌酸激酶（CK）水平。此外，硝苯地平治疗增加了mdx小鼠倒挂握力试验评估的肌肉力量和强迫游泳试验测量的运动耐量。我们假设硝苯地平减少基础ATP释放，从而降低嘌呤能受体的激活，从而降低mdx骨骼肌细胞中的[Ca2+]r。这项工作的结果为药物治疗DMD的可能靶点开辟了新的视角。
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 [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.
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