Mitochondrial dysfunction and apoptosis in myopathic mice with collagen VI deficiency. (Articolo in rivista)

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  • Mitochondrial dysfunction and apoptosis in myopathic mice with collagen VI deficiency. (Articolo in rivista) (literal)
Anno
  • 2003-01-01T00:00:00+01:00 (literal)
Alternative label
  • Irwin WA.1-2-6, Bergamin N.1-6, Sabatelli P.3, Reggiani C.4, Megighian A.4, Merlini L.5, Braghetta P.1, Columbaro M.5, Volpin D.1, Bressan GM, Bernardi P.2, Bonaldo P.1 (2003)
    Mitochondrial dysfunction and apoptosis in myopathic mice with collagen VI deficiency.
    in Nature genetics (Print)
    (literal)
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  • Irwin WA.1-2-6, Bergamin N.1-6, Sabatelli P.3, Reggiani C.4, Megighian A.4, Merlini L.5, Braghetta P.1, Columbaro M.5, Volpin D.1, Bressan GM, Bernardi P.2, Bonaldo P.1 (literal)
Pagina inizio
  • 367 (literal)
Pagina fine
  • 371 (literal)
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  • Lavoro multidisciplinare a carattere preclinico. Il lavoro √® stato oggetto di diverse recensioni sulla letteratura scientifica internazionale, nonch√® di articoli divulgativi sulla stampa nazionale. Le prospettive terapeutiche indicate dai risultati di questo lavoro sono attualmente in valutazione da parte del comitato scientifico Telethon. I.F. 26,711 (literal)
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  • 35 (literal)
Rivista
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  • I.F. 26,711 (literal)
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  • 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 F1F(O)-ATPase inhibitor oligomycin, which caused mitochondrial depolarization, Ca2+ 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. (literal)
Note
  • ISI Web of Science (WOS) (literal)
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  • 1Departments of Histology, Microbiology & Medical Biotechnologies, Uni. Padova 2Department of Biomedical Sciences, Uni. Padova 3ITOI- Sez. Bologna -CNR 4Departments of Human Anatomy & Physiology, Uni. Padova 5Orthopedic Institute 'Rizzoli', Bologna (literal)
Titolo
  • Mitochondrial dysfunction and apoptosis in myopathic mice with collagen VI deficiency. (literal)
Abstract
  • 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 F1F(O)-ATPase inhibitor oligomycin, which caused mitochondrial depolarization, Ca2+ 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. (literal)
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