Cargando…
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,...
Autores principales: | , , , , , , , , |
---|---|
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 |
_version_ | 1783491034327547904 |
---|---|
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. |
format | Online Article Text |
id | pubmed-6981178 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2020 |
publisher | Nature Publishing Group UK |
record_format | MEDLINE/PubMed |
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 |
work_keys_str_mv | AT timpanicaraa adenylosuccinicacidtherapyamelioratesmurineduchennemusculardystrophy AT goodmancraiga adenylosuccinicacidtherapyamelioratesmurineduchennemusculardystrophy AT stathischristosg adenylosuccinicacidtherapyamelioratesmurineduchennemusculardystrophy AT whitejasond adenylosuccinicacidtherapyamelioratesmurineduchennemusculardystrophy AT mamchaouikamel adenylosuccinicacidtherapyamelioratesmurineduchennemusculardystrophy AT butlerbrownegillian adenylosuccinicacidtherapyamelioratesmurineduchennemusculardystrophy AT guevennuri adenylosuccinicacidtherapyamelioratesmurineduchennemusculardystrophy AT hayesalan adenylosuccinicacidtherapyamelioratesmurineduchennemusculardystrophy AT rybalkaemma adenylosuccinicacidtherapyamelioratesmurineduchennemusculardystrophy |