Mitochondrial dysfunction in the pathogenesis of Ullrich congenital muscular dystrophy and prospective therapy with cyclosporins

• Published in: Proceedings of the National Academy of Sciences - PNAS 2007-01, Vol.104 (3), p.991-996
• Main Authors: 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
• Format: Article
• Language: English
• Subjects: Adult; Apoptosis; Biological Sciences; Biopsies; Cell culture techniques; Cells; Cells, Cultured; Child; Child, Preschool; Collagen Type VI - genetics; Collagen Type VI - metabolism; Collagens; Cultured cells; Cyclosporins - therapeutic use; Genetic mutation; Humans; Medical treatment; Microscopy, Electron; Mitochondria; Mitochondria, Muscle - drug effects; Mitochondria, Muscle - metabolism; Muscular diseases; Muscular Dystrophies - congenital; Muscular Dystrophies - drug therapy; Muscular Dystrophies - etiology; Muscular Dystrophies - metabolism; Muscular dystrophy; Musculoskeletal system; Mutation - genetics; Myoblasts; Oligomycins; Pathology
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.0610270104

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 methylAla³ethylVal⁴-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 methylAla³ethylVal⁴ cyclosporin.