title: 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.affiliation: Department of Biomedical Sciences and Institute of Neuroscience, Consiglio Nazionale delle Ricerche, University of Padua, Viale Giuseppe Colombo 3, I-35121 Padua, Italy.
authors.forename: Alessia
authors.initials: A
authors.lastname: Angelin
authors.forename: Tania
authors.initials: T
authors.lastname: Tiepolo
authors.forename: Patrizia
authors.initials: P
authors.lastname: Sabatelli
authors.forename: Paolo
authors.initials: P
authors.lastname: Grumati
authors.forename: Natascha
authors.initials: N
authors.lastname: Bergamin
authors.forename: Cristina
authors.initials: C
authors.lastname: Golfieri
authors.forename: Elisabetta
authors.initials: E
authors.lastname: Mattioli
authors.forename: Francesca
authors.initials: F
authors.lastname: Gualandi
authors.forename: Alessandra
authors.initials: A
authors.lastname: Ferlini
authors.forename: Luciano
authors.initials: L
authors.lastname: Merlini
authors.forename: Nadir M
authors.initials: NM
authors.lastname: Maraldi
authors.forename: Paolo
authors.initials: P
authors.lastname: Bonaldo
authors.forename: Paolo
authors.initials: P
authors.lastname: Bernardi
mesh_terms: D000328:Adult; D017209:Apoptosis; D002478:Cells, Cultured; D002648:Child; D002675:Child, Preschool; D024142:Collagen Type VI / Q000235:genetics / Q000378:metabolism; D003524:Cyclosporins / Q000627:therapeutic use*; D006801:Humans; D008854:Microscopy, Electron; D008931:Mitochondria, Muscle / Q000187:drug effects* / Q000378:metabolism*; D009136:Muscular Dystrophies / Q000151:congenital / Q000188:drug therapy* / Q000209:etiology* / Q000378:metabolism*; D009154:Mutation / Q000235:genetics
chemical_list: D024142:Collagen Type VI; D003524:Cyclosporins