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Prevention of exercised induced cardiomyopathy following Pip-PMO treatment in dystrophic mdx mice

Duchenne muscular dystrophy (DMD) is a fatal neuromuscular disorder caused by mutations in the Dmd gene. In addition to skeletal muscle wasting, DMD patients develop cardiomyopathy, which significantly contributes to mortality. Antisense oligonucleotides (AOs) are a promising DMD therapy, restoring...

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Autores principales: Betts, Corinne A., Saleh, Amer F., Carr, Carolyn A., Hammond, Suzan M., Coenen-Stass, Anna M. L., Godfrey, Caroline, McClorey, Graham, Varela, Miguel A., Roberts, Thomas C., Clarke, Kieran, Gait, Michael J., Wood, Matthew J. A.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group 2015
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4355666/
https://www.ncbi.nlm.nih.gov/pubmed/25758104
http://dx.doi.org/10.1038/srep08986
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author Betts, Corinne A.
Saleh, Amer F.
Carr, Carolyn A.
Hammond, Suzan M.
Coenen-Stass, Anna M. L.
Godfrey, Caroline
McClorey, Graham
Varela, Miguel A.
Roberts, Thomas C.
Clarke, Kieran
Gait, Michael J.
Wood, Matthew J. A.
author_facet Betts, Corinne A.
Saleh, Amer F.
Carr, Carolyn A.
Hammond, Suzan M.
Coenen-Stass, Anna M. L.
Godfrey, Caroline
McClorey, Graham
Varela, Miguel A.
Roberts, Thomas C.
Clarke, Kieran
Gait, Michael J.
Wood, Matthew J. A.
author_sort Betts, Corinne A.
collection PubMed
description Duchenne muscular dystrophy (DMD) is a fatal neuromuscular disorder caused by mutations in the Dmd gene. In addition to skeletal muscle wasting, DMD patients develop cardiomyopathy, which significantly contributes to mortality. Antisense oligonucleotides (AOs) are a promising DMD therapy, restoring functional dystrophin protein by exon skipping. However, a major limitation with current AOs is the absence of dystrophin correction in heart. Pip peptide-AOs demonstrate high activity in cardiac muscle. To determine their therapeutic value, dystrophic mdx mice were subject to forced exercise to model the DMD cardiac phenotype. Repeated peptide-AO treatments resulted in high levels of cardiac dystrophin protein, which prevented the exercised induced progression of cardiomyopathy, normalising heart size as well as stabilising other cardiac parameters. Treated mice also exhibited significantly reduced cardiac fibrosis and improved sarcolemmal integrity. This work demonstrates that high levels of cardiac dystrophin restored by Pip peptide-AOs prevents further deterioration of cardiomyopathy and pathology following exercise in dystrophic DMD mice.
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spelling pubmed-43556662015-03-17 Prevention of exercised induced cardiomyopathy following Pip-PMO treatment in dystrophic mdx mice Betts, Corinne A. Saleh, Amer F. Carr, Carolyn A. Hammond, Suzan M. Coenen-Stass, Anna M. L. Godfrey, Caroline McClorey, Graham Varela, Miguel A. Roberts, Thomas C. Clarke, Kieran Gait, Michael J. Wood, Matthew J. A. Sci Rep Article Duchenne muscular dystrophy (DMD) is a fatal neuromuscular disorder caused by mutations in the Dmd gene. In addition to skeletal muscle wasting, DMD patients develop cardiomyopathy, which significantly contributes to mortality. Antisense oligonucleotides (AOs) are a promising DMD therapy, restoring functional dystrophin protein by exon skipping. However, a major limitation with current AOs is the absence of dystrophin correction in heart. Pip peptide-AOs demonstrate high activity in cardiac muscle. To determine their therapeutic value, dystrophic mdx mice were subject to forced exercise to model the DMD cardiac phenotype. Repeated peptide-AO treatments resulted in high levels of cardiac dystrophin protein, which prevented the exercised induced progression of cardiomyopathy, normalising heart size as well as stabilising other cardiac parameters. Treated mice also exhibited significantly reduced cardiac fibrosis and improved sarcolemmal integrity. This work demonstrates that high levels of cardiac dystrophin restored by Pip peptide-AOs prevents further deterioration of cardiomyopathy and pathology following exercise in dystrophic DMD mice. Nature Publishing Group 2015-03-11 /pmc/articles/PMC4355666/ /pubmed/25758104 http://dx.doi.org/10.1038/srep08986 Text en Copyright © 2015, Macmillan Publishers Limited. All rights reserved http://creativecommons.org/licenses/by/4.0/ This work is licensed under a Creative Commons Attribution 4.0 International License. The images or other third party material in this article are included in the article's Creative Commons license, unless indicated otherwise in the credit line; if the material is not included under the Creative Commons license, users will need to obtain permission from the license holder in order to reproduce the material. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/
spellingShingle Article
Betts, Corinne A.
Saleh, Amer F.
Carr, Carolyn A.
Hammond, Suzan M.
Coenen-Stass, Anna M. L.
Godfrey, Caroline
McClorey, Graham
Varela, Miguel A.
Roberts, Thomas C.
Clarke, Kieran
Gait, Michael J.
Wood, Matthew J. A.
Prevention of exercised induced cardiomyopathy following Pip-PMO treatment in dystrophic mdx mice
title Prevention of exercised induced cardiomyopathy following Pip-PMO treatment in dystrophic mdx mice
title_full Prevention of exercised induced cardiomyopathy following Pip-PMO treatment in dystrophic mdx mice
title_fullStr Prevention of exercised induced cardiomyopathy following Pip-PMO treatment in dystrophic mdx mice
title_full_unstemmed Prevention of exercised induced cardiomyopathy following Pip-PMO treatment in dystrophic mdx mice
title_short Prevention of exercised induced cardiomyopathy following Pip-PMO treatment in dystrophic mdx mice
title_sort prevention of exercised induced cardiomyopathy following pip-pmo treatment in dystrophic mdx mice
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4355666/
https://www.ncbi.nlm.nih.gov/pubmed/25758104
http://dx.doi.org/10.1038/srep08986
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