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Testing of therapies in a novel nebulin nemaline myopathy model demonstrate a lack of efficacy

Nemaline myopathies are heterogeneous congenital muscle disorders causing skeletal muscle weakness and, in some cases, death soon after birth. Mutations in nebulin, encoding a large sarcomeric protein required for thin filament function, are responsible for approximately 50% of nemaline myopathy cas...

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Autores principales: Sztal, Tamar E., McKaige, Emily A., Williams, Caitlin, Oorschot, Viola, Ramm, Georg, Bryson-Richardson, Robert J.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: BioMed Central 2018
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5977763/
https://www.ncbi.nlm.nih.gov/pubmed/29848386
http://dx.doi.org/10.1186/s40478-018-0546-9
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author Sztal, Tamar E.
McKaige, Emily A.
Williams, Caitlin
Oorschot, Viola
Ramm, Georg
Bryson-Richardson, Robert J.
author_facet Sztal, Tamar E.
McKaige, Emily A.
Williams, Caitlin
Oorschot, Viola
Ramm, Georg
Bryson-Richardson, Robert J.
author_sort Sztal, Tamar E.
collection PubMed
description Nemaline myopathies are heterogeneous congenital muscle disorders causing skeletal muscle weakness and, in some cases, death soon after birth. Mutations in nebulin, encoding a large sarcomeric protein required for thin filament function, are responsible for approximately 50% of nemaline myopathy cases. Despite the severity of the disease there is no effective treatment for nemaline myopathy with limited research to develop potential therapies. Several supplements, including L-tyrosine, have been suggested to be beneficial and consequently self-administered by nemaline myopathy patients without any knowledge of their efficacy. We have characterized a zebrafish model for nemaline myopathy caused by a mutation in nebulin. These fish form electron-dense nemaline bodies and display reduced muscle function akin to the phenotypes observed in nemaline myopathy patients. We have utilized our zebrafish model to test and evaluate four treatments currently self-administered by nemaline myopathy patients to determine their ability to increase skeletal muscle function. Analysis of muscle pathology and locomotion following treatment with L-tyrosine, L-carnitine, taurine, or creatine revealed no significant improvement in skeletal muscle function emphasizing the urgency to develop effective therapies for nemaline myopathy. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (10.1186/s40478-018-0546-9) contains supplementary material, which is available to authorized users.
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spelling pubmed-59777632018-06-06 Testing of therapies in a novel nebulin nemaline myopathy model demonstrate a lack of efficacy Sztal, Tamar E. McKaige, Emily A. Williams, Caitlin Oorschot, Viola Ramm, Georg Bryson-Richardson, Robert J. Acta Neuropathol Commun Research Nemaline myopathies are heterogeneous congenital muscle disorders causing skeletal muscle weakness and, in some cases, death soon after birth. Mutations in nebulin, encoding a large sarcomeric protein required for thin filament function, are responsible for approximately 50% of nemaline myopathy cases. Despite the severity of the disease there is no effective treatment for nemaline myopathy with limited research to develop potential therapies. Several supplements, including L-tyrosine, have been suggested to be beneficial and consequently self-administered by nemaline myopathy patients without any knowledge of their efficacy. We have characterized a zebrafish model for nemaline myopathy caused by a mutation in nebulin. These fish form electron-dense nemaline bodies and display reduced muscle function akin to the phenotypes observed in nemaline myopathy patients. We have utilized our zebrafish model to test and evaluate four treatments currently self-administered by nemaline myopathy patients to determine their ability to increase skeletal muscle function. Analysis of muscle pathology and locomotion following treatment with L-tyrosine, L-carnitine, taurine, or creatine revealed no significant improvement in skeletal muscle function emphasizing the urgency to develop effective therapies for nemaline myopathy. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (10.1186/s40478-018-0546-9) contains supplementary material, which is available to authorized users. BioMed Central 2018-05-30 /pmc/articles/PMC5977763/ /pubmed/29848386 http://dx.doi.org/10.1186/s40478-018-0546-9 Text en © The Author(s). 2018 Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.
spellingShingle Research
Sztal, Tamar E.
McKaige, Emily A.
Williams, Caitlin
Oorschot, Viola
Ramm, Georg
Bryson-Richardson, Robert J.
Testing of therapies in a novel nebulin nemaline myopathy model demonstrate a lack of efficacy
title Testing of therapies in a novel nebulin nemaline myopathy model demonstrate a lack of efficacy
title_full Testing of therapies in a novel nebulin nemaline myopathy model demonstrate a lack of efficacy
title_fullStr Testing of therapies in a novel nebulin nemaline myopathy model demonstrate a lack of efficacy
title_full_unstemmed Testing of therapies in a novel nebulin nemaline myopathy model demonstrate a lack of efficacy
title_short Testing of therapies in a novel nebulin nemaline myopathy model demonstrate a lack of efficacy
title_sort testing of therapies in a novel nebulin nemaline myopathy model demonstrate a lack of efficacy
topic Research
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5977763/
https://www.ncbi.nlm.nih.gov/pubmed/29848386
http://dx.doi.org/10.1186/s40478-018-0546-9
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