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Zebrafish models of collagen VI-related myopathies

Collagen VI is an integral part of the skeletal muscle extracellular matrix, providing mechanical stability and facilitating matrix-dependent cell signaling. Mutations in collagen VI result in either Ullrich congenital muscular dystrophy (UCMD) or Bethlem myopathy (BM), with UCMD being clinically mo...

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Autores principales: Telfer, W.R., Busta, A.S., Bonnemann, C.G., Feldman, E.L., Dowling, J.J.
Formato: Texto
Lenguaje:English
Publicado: Oxford University Press 2010
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2876888/
https://www.ncbi.nlm.nih.gov/pubmed/20338942
http://dx.doi.org/10.1093/hmg/ddq126
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author Telfer, W.R.
Busta, A.S.
Bonnemann, C.G.
Feldman, E.L.
Dowling, J.J.
author_facet Telfer, W.R.
Busta, A.S.
Bonnemann, C.G.
Feldman, E.L.
Dowling, J.J.
author_sort Telfer, W.R.
collection PubMed
description Collagen VI is an integral part of the skeletal muscle extracellular matrix, providing mechanical stability and facilitating matrix-dependent cell signaling. Mutations in collagen VI result in either Ullrich congenital muscular dystrophy (UCMD) or Bethlem myopathy (BM), with UCMD being clinically more severe. Recent studies demonstrating increased apoptosis and abnormal mitochondrial function in Col6a1 knockout mice and in human myoblasts have provided the first mechanistic insights into the pathophysiology of these diseases. However, how loss of collagen VI causes mitochondrial dysfunction remains to be understood. Progress is hindered in part by the lack of an adequate animal model for UCMD, as knockout mice have a mild motor phenotype. To further the understanding of these disorders, we have generated zebrafish models of the collagen VI myopathies. Morpholinos designed to exon 9 of col6a1 produced a severe muscle disease reminiscent of UCMD, while ones to exon 13 produced a milder phenotype similar to BM. UCMD-like zebrafish have increased cell death and abnormal mitochondria, which can be attenuated by treatment with the proton pump modifier cyclosporin A (CsA). CsA improved the motor deficits in UCMD-like zebrafish, but failed to reverse the sarcolemmal membrane damage. In all, we have successfully generated the first vertebrate model matching the clinical severity of UCMD and demonstrated that CsA provides phenotypic improvement, thus corroborating data from knockout mice supporting the use of mitochondrial permeability transition pore modifiers as therapeutics in patients, and providing proof of principle for the utility of the zebrafish as a powerful preclinical model.
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spelling pubmed-28768882010-05-27 Zebrafish models of collagen VI-related myopathies Telfer, W.R. Busta, A.S. Bonnemann, C.G. Feldman, E.L. Dowling, J.J. Hum Mol Genet Articles Collagen VI is an integral part of the skeletal muscle extracellular matrix, providing mechanical stability and facilitating matrix-dependent cell signaling. Mutations in collagen VI result in either Ullrich congenital muscular dystrophy (UCMD) or Bethlem myopathy (BM), with UCMD being clinically more severe. Recent studies demonstrating increased apoptosis and abnormal mitochondrial function in Col6a1 knockout mice and in human myoblasts have provided the first mechanistic insights into the pathophysiology of these diseases. However, how loss of collagen VI causes mitochondrial dysfunction remains to be understood. Progress is hindered in part by the lack of an adequate animal model for UCMD, as knockout mice have a mild motor phenotype. To further the understanding of these disorders, we have generated zebrafish models of the collagen VI myopathies. Morpholinos designed to exon 9 of col6a1 produced a severe muscle disease reminiscent of UCMD, while ones to exon 13 produced a milder phenotype similar to BM. UCMD-like zebrafish have increased cell death and abnormal mitochondria, which can be attenuated by treatment with the proton pump modifier cyclosporin A (CsA). CsA improved the motor deficits in UCMD-like zebrafish, but failed to reverse the sarcolemmal membrane damage. In all, we have successfully generated the first vertebrate model matching the clinical severity of UCMD and demonstrated that CsA provides phenotypic improvement, thus corroborating data from knockout mice supporting the use of mitochondrial permeability transition pore modifiers as therapeutics in patients, and providing proof of principle for the utility of the zebrafish as a powerful preclinical model. Oxford University Press 2010-06-15 2010-03-25 /pmc/articles/PMC2876888/ /pubmed/20338942 http://dx.doi.org/10.1093/hmg/ddq126 Text en © The Author 2010. Published by Oxford University Press http://creativecommons.org/licenses/by-nc/2.0/uk/ This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/2.5), which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.
spellingShingle Articles
Telfer, W.R.
Busta, A.S.
Bonnemann, C.G.
Feldman, E.L.
Dowling, J.J.
Zebrafish models of collagen VI-related myopathies
title Zebrafish models of collagen VI-related myopathies
title_full Zebrafish models of collagen VI-related myopathies
title_fullStr Zebrafish models of collagen VI-related myopathies
title_full_unstemmed Zebrafish models of collagen VI-related myopathies
title_short Zebrafish models of collagen VI-related myopathies
title_sort zebrafish models of collagen vi-related myopathies
topic Articles
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2876888/
https://www.ncbi.nlm.nih.gov/pubmed/20338942
http://dx.doi.org/10.1093/hmg/ddq126
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