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

Abstract

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.

• Authors: Alessia Angelin, Tania Tiepolo, Patrizia Sabatelli, Paolo Grumati, Natascha Bergamin, Cristina Golfieri, Elisabetta Mattioli, Francesca Gualandi, Alessandra Ferlini, Luciano Merlini, Nadir M Maraldi, Paolo Bonaldo, Paolo Bernardi
• Journal: Proceedings of the National Academy of Sciences of the United States of America (Proc Natl Acad Sci U S A) Vol. 104 Issue 3 Pg. 991-6 (Jan 16 2007) ISSN: 0027-8424 [Print] United States
• PMID: 17215366 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Collagen Type VI
• Cyclosporins

Topics

• Adult
• Apoptosis
• Cells, Cultured
• Child
• Child, Preschool
• Collagen Type VI (genetics, metabolism)
• Cyclosporins (therapeutic use)
• Humans
• Microscopy, Electron
• Mitochondria, Muscle (drug effects, metabolism)
• Muscular Dystrophies (congenital, drug therapy, etiology, metabolism)
• Mutation (genetics)