Angelin Alessia, Tiepolo Tania, Sabatelli Patrizia, Grumati Paolo, Bergamin Natascha, Golfieri Cristina, Mattioli Elisabetta, Gualandi Francesca, Ferlini Alessandra, Merlini Luciano, Maraldi Nadir M, Bonaldo Paolo, Bernardi Paolo
Department of Biomedical Sciences and Institute of Neuroscience, Consiglio Nazionale delle Ricerche, University of Padua, Viale Giuseppe Colombo 3, I-35121 Padua, Italy.
Proc Natl Acad Sci U S A. 2007 Jan 16;104(3):991-6. doi: 10.1073/pnas.0610270104. Epub 2007 Jan 10.
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 Ca(2+) 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.
乌尔里希先天性肌营养不良是一种严重的、在遗传和临床方面具有异质性的肌肉疾病，与胶原蛋白VI缺乏有关。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肌营养不良中肌纤维死亡起始过程中的潜在作用，我们研究了从患有不同胶原蛋白VI基因缺陷及该疾病不同临床表现的患者身上获取的活检组织和成肌细胞培养物。我们在乌尔里希先天性肌营养不良患者的成肌细胞中发现了一种潜在的线粒体功能障碍，这与自发凋亡发生率的增加相匹配。与健康供体的成肌细胞不同，患者细胞中的线粒体在添加寡霉素后发生去极化，并表现出超微结构改变，而寡霉素处理会使这种改变恶化。增加的凋亡、超微结构缺陷以及对寡霉素的异常反应可通过钙离子螯合剂、将细胞接种在胶原蛋白VI上、用环孢素A或用不影响钙调神经磷酸酶活性的特异性亲环蛋白抑制剂甲基丙氨酸（3）乙基缬氨酸（4） - 环孢素来使其恢复正常。在此，我们证明线粒体功能障碍在乌尔里希先天性肌营养不良的肌肉细胞消耗中起重要作用。这项研究是朝着用环孢素A和甲基丙氨酸（3）乙基缬氨酸（4）环孢素对乌尔里希先天性肌营养不良进行药物治疗迈出的重要一步。
