Lack of Correlation between Outcomes of Membrane Repair Assay and Correction of Dystrophic Changes in Experimental Therapeutic Strategy in Dysferlinopathy

Hdl Handle:
http://hdl.handle.net/10675.2/712
Title:
Lack of Correlation between Outcomes of Membrane Repair Assay and Correction of Dystrophic Changes in Experimental Therapeutic Strategy in Dysferlinopathy
Authors:
Lostal, William; Bartoli, Marc ( 0000-0003-3339-9858 ) ; Roudaut, Carinne; Bourg, Nathalie; Krahn, Martin; Pryadkina, Marina; Borel, Perrine; Suel, Laurence; Roche, Joseph A.; Stockholm, Daniel; Bloch, Robert J.; Levy, Nicolas; Bashir, Rumaisa; Richard, Isabelle
Abstract:
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 fullfiling 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.
Editors:
McNeil, Paul L.
Citation:
PLoS One. 2012 May 29; 7(5):e38036
Issue Date:
29-May-2012
URI:
http://hdl.handle.net/10675.2/712
DOI:
10.1371/journal.pone.0038036
PubMed ID:
22666441
PubMed Central ID:
PMC3362551
Type:
Article
ISSN:
1932-6203
Appears in Collections:
Department of Cellular Biology and Anatomy Faculty Papers

Full metadata record

DC FieldValue Language
dc.contributor.authorLostal, Williamen_US
dc.contributor.authorBartoli, Marcen_US
dc.contributor.authorRoudaut, Carinneen_US
dc.contributor.authorBourg, Nathalieen_US
dc.contributor.authorKrahn, Martinen_US
dc.contributor.authorPryadkina, Marinaen_US
dc.contributor.authorBorel, Perrineen_US
dc.contributor.authorSuel, Laurenceen_US
dc.contributor.authorRoche, Joseph A.en_US
dc.contributor.authorStockholm, Danielen_US
dc.contributor.authorBloch, Robert J.en_US
dc.contributor.authorLevy, Nicolasen_US
dc.contributor.authorBashir, Rumaisaen_US
dc.contributor.authorRichard, Isabelleen_US
dc.contributor.editorMcNeil, Paul L.-
dc.date.accessioned2012-10-26T16:40:51Z-
dc.date.available2012-10-26T16:40:51Z-
dc.date.issued2012-05-29en_US
dc.identifier.citationPLoS One. 2012 May 29; 7(5):e38036en_US
dc.identifier.issn1932-6203en_US
dc.identifier.pmid22666441en_US
dc.identifier.doi10.1371/journal.pone.0038036en_US
dc.identifier.urihttp://hdl.handle.net/10675.2/712-
dc.description.abstractMutations 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 fullfiling 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.en_US
dc.rightsLostal et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.en_US
dc.subjectResearch Articleen_US
dc.subjectBiologyen_US
dc.subjectAnatomy and Physiologyen_US
dc.subjectMusculoskeletal Systemen_US
dc.subjectMuscleen_US
dc.subjectMuscle Biochemistryen_US
dc.subjectMuscle Typesen_US
dc.subjectCell Physiologyen_US
dc.subjectModel Organismsen_US
dc.subjectAnimal Modelsen_US
dc.subjectMouseen_US
dc.subjectMedicineen_US
dc.subjectAnatomy and Physiologyen_US
dc.subjectMusculoskeletal Systemen_US
dc.subjectMuscleen_US
dc.subjectMuscle Biochemistryen_US
dc.subjectMuscle Typesen_US
dc.subjectNeurologyen_US
dc.subjectMuscular Dystrophiesen_US
dc.titleLack of Correlation between Outcomes of Membrane Repair Assay and Correction of Dystrophic Changes in Experimental Therapeutic Strategy in Dysferlinopathyen_US
dc.typeArticleen_US
dc.identifier.pmcidPMC3362551en_US
dc.contributor.corporatenameDepartment of Cellular Biology and Anatomy-
dc.contributor.corporatenameCollege of Graduate Studies-

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