Mitochondrial dysfunction and apoptosis in myopathic mice with collagen VI deficiency

William A. Irwin, Natascha Bergamin, Patrizia Sabatelli, Carlo Reggiani, Aram Megighian, Luciano Merlini, Paola Braghetta, Marta Columbaro, Dino Volpin, Giorgio M. Bressan, Paolo Bernardi, Paolo Bonaldo

Research output: Contribution to journalArticlepeer-review


Collagen VI is an extracellular matrix protein that forms a microfilamentous network in skeletal muscles and other organs. Inherited mutations in genes encoding collagen VI in humans cause two muscle diseases, Bethlem myopathy and Ullrich congenital muscular dystrophy. We previously generated collagen VI-deficient (Col6a1-/-) mice and showed that they have a muscle phenotype that strongly resembles Bethlem myopathy. The pathophysiological defects and mechanisms leading to the myopathic disorder were not known. Here we show that Col6a1-/- muscles have a loss of contractile strength associated with ultrastructural alterations of sarcoplasmic reticulum (SR) and mitochondria and spontaneous apoptosis. We found a latent mitochondrial dysfunction in myofibers of Col6a1-/- mice on incubation with the selective F1FO-ATPase inhibitor oligomycin, which caused mitochondrial depolarization, Ca 2+ deregulation and increased apoptosis. These defects were reversible, as they could be normalized by plating Col6a1-/- myofibers on collagen VI or by addition of cyclosporin A (CsA), the inhibitor of mitochondrial permeability transition pore (PTP). Treatment of Col6a1 -/- mice with CsA rescued the muscle ultrastructural defects and markedly decreased the number of apoptotic nuclei in vivo. These findings indicate that collagen VI myopathies have an unexpected mitochondrial pathogenesis that could be exploited for therapeutic intervention.

Original languageEnglish
Pages (from-to)367-371
Number of pages5
JournalNature Genetics
Issue number4
Publication statusPublished - Dec 2003

ASJC Scopus subject areas

  • Genetics(clinical)
  • Genetics


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