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Adenylosuccinic acid therapy ameliorates murine Duchenne Muscular Dystrophy

Arising from the ablation of the cytoskeletal protein dystrophin, Duchenne Muscular Dystrophy (DMD) is a debilitating and fatal skeletal muscle wasting disease underpinned by metabolic insufficiency. The inability to facilitate adequate energy production may impede calcium (Ca(2+)) buffering within,...

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Autores principales: Timpani, Cara A., Goodman, Craig A., Stathis, Christos G., White, Jason D., Mamchaoui, Kamel, Butler-Browne, Gillian, Gueven, Nuri, Hayes, Alan, Rybalka, Emma
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group UK 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6981178/
https://www.ncbi.nlm.nih.gov/pubmed/31980663
http://dx.doi.org/10.1038/s41598-020-57610-w
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author Timpani, Cara A.
Goodman, Craig A.
Stathis, Christos G.
White, Jason D.
Mamchaoui, Kamel
Butler-Browne, Gillian
Gueven, Nuri
Hayes, Alan
Rybalka, Emma
author_facet Timpani, Cara A.
Goodman, Craig A.
Stathis, Christos G.
White, Jason D.
Mamchaoui, Kamel
Butler-Browne, Gillian
Gueven, Nuri
Hayes, Alan
Rybalka, Emma
author_sort Timpani, Cara A.
collection PubMed
description Arising from the ablation of the cytoskeletal protein dystrophin, Duchenne Muscular Dystrophy (DMD) is a debilitating and fatal skeletal muscle wasting disease underpinned by metabolic insufficiency. The inability to facilitate adequate energy production may impede calcium (Ca(2+)) buffering within, and the regenerative capacity of, dystrophic muscle. Therefore, increasing the metabogenic potential could represent an effective treatment avenue. The aim of our study was to determine the efficacy of adenylosuccinic acid (ASA), a purine nucleotide cycle metabolite, to stimulate metabolism and buffer skeletal muscle damage in the mdx mouse model of DMD. Dystrophin-positive control (C57BL/10) and dystrophin-deficient mdx mice were treated with ASA (3000 µg.mL(−1)) in drinking water. Following the 8-week treatment period, metabolism, mitochondrial density, viability and superoxide (O(2)(−)) production, as well as skeletal muscle histopathology, were assessed. ASA treatment significantly improved the histopathological features of murine DMD by reducing damage area, the number of centronucleated fibres, lipid accumulation, connective tissue infiltration and Ca(2+) content of mdx tibialis anterior. These effects were independent of upregulated utrophin expression in the tibialis anterior. ASA treatment also increased mitochondrial viability in mdx flexor digitorum brevis fibres and concomitantly reduced O(2)(−) production, an effect that was also observed in cultured immortalised human DMD myoblasts. Our data indicates that ASA has a protective effect on mdx skeletal muscles.
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spelling pubmed-69811782020-01-30 Adenylosuccinic acid therapy ameliorates murine Duchenne Muscular Dystrophy Timpani, Cara A. Goodman, Craig A. Stathis, Christos G. White, Jason D. Mamchaoui, Kamel Butler-Browne, Gillian Gueven, Nuri Hayes, Alan Rybalka, Emma Sci Rep Article Arising from the ablation of the cytoskeletal protein dystrophin, Duchenne Muscular Dystrophy (DMD) is a debilitating and fatal skeletal muscle wasting disease underpinned by metabolic insufficiency. The inability to facilitate adequate energy production may impede calcium (Ca(2+)) buffering within, and the regenerative capacity of, dystrophic muscle. Therefore, increasing the metabogenic potential could represent an effective treatment avenue. The aim of our study was to determine the efficacy of adenylosuccinic acid (ASA), a purine nucleotide cycle metabolite, to stimulate metabolism and buffer skeletal muscle damage in the mdx mouse model of DMD. Dystrophin-positive control (C57BL/10) and dystrophin-deficient mdx mice were treated with ASA (3000 µg.mL(−1)) in drinking water. Following the 8-week treatment period, metabolism, mitochondrial density, viability and superoxide (O(2)(−)) production, as well as skeletal muscle histopathology, were assessed. ASA treatment significantly improved the histopathological features of murine DMD by reducing damage area, the number of centronucleated fibres, lipid accumulation, connective tissue infiltration and Ca(2+) content of mdx tibialis anterior. These effects were independent of upregulated utrophin expression in the tibialis anterior. ASA treatment also increased mitochondrial viability in mdx flexor digitorum brevis fibres and concomitantly reduced O(2)(−) production, an effect that was also observed in cultured immortalised human DMD myoblasts. Our data indicates that ASA has a protective effect on mdx skeletal muscles. Nature Publishing Group UK 2020-01-24 /pmc/articles/PMC6981178/ /pubmed/31980663 http://dx.doi.org/10.1038/s41598-020-57610-w Text en © The Author(s) 2020 Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as 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 images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
spellingShingle Article
Timpani, Cara A.
Goodman, Craig A.
Stathis, Christos G.
White, Jason D.
Mamchaoui, Kamel
Butler-Browne, Gillian
Gueven, Nuri
Hayes, Alan
Rybalka, Emma
Adenylosuccinic acid therapy ameliorates murine Duchenne Muscular Dystrophy
title Adenylosuccinic acid therapy ameliorates murine Duchenne Muscular Dystrophy
title_full Adenylosuccinic acid therapy ameliorates murine Duchenne Muscular Dystrophy
title_fullStr Adenylosuccinic acid therapy ameliorates murine Duchenne Muscular Dystrophy
title_full_unstemmed Adenylosuccinic acid therapy ameliorates murine Duchenne Muscular Dystrophy
title_short Adenylosuccinic acid therapy ameliorates murine Duchenne Muscular Dystrophy
title_sort adenylosuccinic acid therapy ameliorates murine duchenne muscular dystrophy
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6981178/
https://www.ncbi.nlm.nih.gov/pubmed/31980663
http://dx.doi.org/10.1038/s41598-020-57610-w
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