Lack of correlation between outcomes of membrane repair assay and correction of dystrophic changes in experimental therapeutic strategy in dysferlinopathy.

Mutations in the dysferlin gene are the cause of Limb-girdle Muscular Dystrophy type 2B and Miyoshi Myopathy. The dysferlin protein has been implicated in sarcolemmal resealing, leading to the idea that the pathophysiology of dysferlin deficiencies is due to a deficit in membrane repair. Here, we sh...

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Autores principales:	William Lostal, Marc Bartoli, Carinne Roudaut, Nathalie Bourg, Martin Krahn, Marina Pryadkina, Perrine Borel, Laurence Suel, Joseph A Roche, Daniel Stockholm, Robert J Bloch, Nicolas Levy, Rumaisa Bashir, Isabelle Richard
Formato:	article
Lenguaje:	EN
Publicado:	Public Library of Science (PLoS) 2012
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/ab23a3d6ce924c7caaba2d978af7e9af
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spelling	oai:doaj.org-article:ab23a3d6ce924c7caaba2d978af7e9af2021-11-18T07:17:04ZLack of correlation between outcomes of membrane repair assay and correction of dystrophic changes in experimental therapeutic strategy in dysferlinopathy.1932-620310.1371/journal.pone.0038036https://doaj.org/article/ab23a3d6ce924c7caaba2d978af7e9af2012-01-01T00:00:00Zhttps://www.ncbi.nlm.nih.gov/pmc/articles/pmid/22666441/?tool=EBIhttps://doaj.org/toc/1932-6203Mutations in the dysferlin gene are the cause of Limb-girdle Muscular Dystrophy type 2B and Miyoshi Myopathy. The dysferlin protein has been implicated in sarcolemmal resealing, leading to the idea that the pathophysiology of dysferlin deficiencies is due to a deficit in membrane repair. Here, we show using two different approaches that fulfilling membrane repair as asseyed by laser wounding assay is not sufficient for alleviating the dysferlin deficient pathology. First, we generated a transgenic mouse overexpressing myoferlin to test the hypothesis that myoferlin, which is homologous to dysferlin, can compensate for the absence of dysferlin. The myoferlin overexpressors show no skeletal muscle abnormalities, and crossing them with a dysferlin-deficient model rescues the membrane fusion defect present in dysferlin-deficient mice in vitro. However, myoferlin overexpression does not correct muscle histology in vivo. Second, we report that AAV-mediated transfer of a minidysferlin, previously shown to correct the membrane repair deficit in vitro, also fails to improve muscle histology. Furthermore, neither myoferlin nor the minidysferlin prevented myofiber degeneration following eccentric exercise. Our data suggest that the pathogenicity of dysferlin deficiency is not solely related to impairment in sarcolemmal repair and highlight the care needed in selecting assays to assess potential therapies for dysferlinopathies.William LostalMarc BartoliCarinne RoudautNathalie BourgMartin KrahnMarina PryadkinaPerrine BorelLaurence SuelJoseph A RocheDaniel StockholmRobert J BlochNicolas LevyRumaisa BashirIsabelle RichardPublic Library of Science (PLoS)articleMedicineRScienceQENPLoS ONE, Vol 7, Iss 5, p e38036 (2012)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q William Lostal Marc Bartoli Carinne Roudaut Nathalie Bourg Martin Krahn Marina Pryadkina Perrine Borel Laurence Suel Joseph A Roche Daniel Stockholm Robert J Bloch Nicolas Levy Rumaisa Bashir Isabelle Richard Lack of correlation between outcomes of membrane repair assay and correction of dystrophic changes in experimental therapeutic strategy in dysferlinopathy.
description	Mutations in the dysferlin gene are the cause of Limb-girdle Muscular Dystrophy type 2B and Miyoshi Myopathy. The dysferlin protein has been implicated in sarcolemmal resealing, leading to the idea that the pathophysiology of dysferlin deficiencies is due to a deficit in membrane repair. Here, we show using two different approaches that fulfilling membrane repair as asseyed by laser wounding assay is not sufficient for alleviating the dysferlin deficient pathology. First, we generated a transgenic mouse overexpressing myoferlin to test the hypothesis that myoferlin, which is homologous to dysferlin, can compensate for the absence of dysferlin. The myoferlin overexpressors show no skeletal muscle abnormalities, and crossing them with a dysferlin-deficient model rescues the membrane fusion defect present in dysferlin-deficient mice in vitro. However, myoferlin overexpression does not correct muscle histology in vivo. Second, we report that AAV-mediated transfer of a minidysferlin, previously shown to correct the membrane repair deficit in vitro, also fails to improve muscle histology. Furthermore, neither myoferlin nor the minidysferlin prevented myofiber degeneration following eccentric exercise. Our data suggest that the pathogenicity of dysferlin deficiency is not solely related to impairment in sarcolemmal repair and highlight the care needed in selecting assays to assess potential therapies for dysferlinopathies.
format	article
author	William Lostal Marc Bartoli Carinne Roudaut Nathalie Bourg Martin Krahn Marina Pryadkina Perrine Borel Laurence Suel Joseph A Roche Daniel Stockholm Robert J Bloch Nicolas Levy Rumaisa Bashir Isabelle Richard
author_facet	William Lostal Marc Bartoli Carinne Roudaut Nathalie Bourg Martin Krahn Marina Pryadkina Perrine Borel Laurence Suel Joseph A Roche Daniel Stockholm Robert J Bloch Nicolas Levy Rumaisa Bashir Isabelle Richard
author_sort	William Lostal
title	Lack of correlation between outcomes of membrane repair assay and correction of dystrophic changes in experimental therapeutic strategy in dysferlinopathy.
title_short	Lack of correlation between outcomes of membrane repair assay and correction of dystrophic changes in experimental therapeutic strategy in dysferlinopathy.
title_full	Lack of correlation between outcomes of membrane repair assay and correction of dystrophic changes in experimental therapeutic strategy in dysferlinopathy.
title_fullStr	Lack of correlation between outcomes of membrane repair assay and correction of dystrophic changes in experimental therapeutic strategy in dysferlinopathy.
title_full_unstemmed	Lack of correlation between outcomes of membrane repair assay and correction of dystrophic changes in experimental therapeutic strategy in dysferlinopathy.
title_sort	lack of correlation between outcomes of membrane repair assay and correction of dystrophic changes in experimental therapeutic strategy in dysferlinopathy.
publisher	Public Library of Science (PLoS)
publishDate	2012
url	https://doaj.org/article/ab23a3d6ce924c7caaba2d978af7e9af
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Lack of correlation between outcomes of membrane repair assay and correction of dystrophic changes in experimental therapeutic strategy in dysferlinopathy.

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