Mitochondrial dysfunction in the pathogenesis of Ullrich congenital muscular dystrophy and prospective therapy with cyclosporins
Mitochondrial dysfunction in the pathogenesis of Ullrich congenital muscular dystrophy and prospective therapy with cyclosporins
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DOI：
10.1073/pnas.0610270104
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发表时间：
2007-01-16
影响因子：
11.1
通讯作者：
Bernardi, Paolo
中科院分区：
文献类型：
--
作者：
Angelin, Alessia;Tiepolo, Tania;Bernardi, Paolo
乌尔里希先天性肌营养不良症是一种与VI型胶原蛋白缺乏有关的严重遗传和临床异质性肌肉疾病。该病的发病机制尚不清楚。为了评估线粒体功能障碍在这种形式的营养不良中肌纤维死亡的发病中的潜在作用，我们研究了从具有不同VI型胶原遗传缺陷和该疾病的可变临床表现的患者中获得的活检和成肌细胞培养物。我们确定了一个潜在的线粒体功能障碍，成肌细胞与乌尔里希先天性肌营养不良症患者，匹配的自发性细胞凋亡的发生率增加。与来自健康供体的成肌细胞不同，来自患者的细胞中的线粒体在加入寡霉素后去极化，并显示出通过寡霉素治疗而恶化的超微结构改变。细胞凋亡增加、超微结构缺陷和对寡霉素的异常反应可通过Ca 2+螯合剂、将细胞接种在胶原VI上以及用环孢菌素A或特异性亲环蛋白抑制剂甲基Ala（3）乙基Val（4）-环孢菌素（其不影响钙调磷酸酶活性）治疗而正常化。在这里，我们证明线粒体功能障碍在乌尔里希先天性肌营养不良症的肌细胞萎缩中起着重要作用。本研究代表了用环孢菌素A和甲基Ala（3）乙基Val（4）-环孢菌素治疗Ullrich先天性肌营养不良症的重要一步。
Ullrich congenital muscular dystrophy is a severe genetically and clinically heterogeneous muscle disorder linked to collagen VI deficiency. The pathogenesis of the disease is unknown. To assess the potential role of mitochondrial dysfunction in the onset of muscle fiber death in this form of dystrophy, we studied biopsies and myoblast cultures obtained from patients with different genetic defects of collagen VI and variable clinical presentations of the disease. We identified a latent mitochondrial dysfunction in myoblasts from patients with Ullrich congenital muscular dystrophy that matched an increased occurrence of spontaneous apoptosis. Unlike those in myoblasts from healthy donors, mitochondria in cells from patients depolarized upon addition of oligomycin and displayed ultrastructural alterations that were worsened by treatment with oligomycin. The increased apoptosis, the ultrastructural defects, and the anomalous response to oligomycin could be normalized by Ca2+ chelators, by plating cells on collagen VI, and by treatment with cyclosporin A or with the specific cyclophilin inhibitor methylAla(3)ethylVal(4)-cyclosporin, which does not affect calcineurin activity. Here we demonstrate that mitochondrial dysfunction plays an important role in muscle cell wasting in Ullrich congenital muscular dystrophy. This study represents an essential step toward a pharmacological therapy of Ullrich congenital muscular dystrophy with cyclosporin A and methylAla(3)ethylVal(4)-cyclosporin.