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Metformin Increases Sarcolemma Integrity and Ameliorates Neuromuscular Deficits in a Murine Model of Duchenne Muscular Dystrophy

Duchenne muscular dystrophy (DMD) is a genetic neuromuscular disease characterized by progressive muscle weakness and wasting. Stimulation of AMP-activated protein kinase (AMPK) has been demonstrated to increase muscle function and protect muscle against damage in dystrophic mice. Metformin is a wid...

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Autores principales: Dong, Xia, Hui, Tiankun, Chen, Jie, Yu, Zheng, Ren, Dongyan, Zou, Suqi, Wang, Shunqi, Fei, Erkang, Jiao, Huifeng, Lai, Xinsheng
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8126699/
https://www.ncbi.nlm.nih.gov/pubmed/34012406
http://dx.doi.org/10.3389/fphys.2021.642908
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author Dong, Xia
Hui, Tiankun
Chen, Jie
Yu, Zheng
Ren, Dongyan
Zou, Suqi
Wang, Shunqi
Fei, Erkang
Jiao, Huifeng
Lai, Xinsheng
author_facet Dong, Xia
Hui, Tiankun
Chen, Jie
Yu, Zheng
Ren, Dongyan
Zou, Suqi
Wang, Shunqi
Fei, Erkang
Jiao, Huifeng
Lai, Xinsheng
author_sort Dong, Xia
collection PubMed
description Duchenne muscular dystrophy (DMD) is a genetic neuromuscular disease characterized by progressive muscle weakness and wasting. Stimulation of AMP-activated protein kinase (AMPK) has been demonstrated to increase muscle function and protect muscle against damage in dystrophic mice. Metformin is a widely used anti-hyperglycemic drug and has been shown to be an indirect activator of AMPK. Based on these findings, we sought to determine the effects of metformin on neuromuscular deficits in mdx murine model of DMD. In this study, we found metformin treatment increased muscle strength accompanied by elevated twitch and tetanic force of tibialis anterior (TA) muscle in mdx mice. Immunofluorescence and electron microscopy analysis of metformin-treated mdx muscles revealed an improvement in muscle fiber membrane integrity. Electrophysiological studies showed the amplitude of miniature endplate potentials (mEPP) was increased in treated mice, indicating metformin also improved neuromuscular transmission of the mdx mice. Analysis of mRNA and protein levels from muscles of treated mice showed an upregulation of AMPK phosphorylation and dystrophin-glycoprotein complex protein expression. In conclusion, metformin can indeed improve muscle function and diminish neuromuscular deficits in mdx mice, suggesting its potential use as a therapeutic drug in DMD patients.
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spelling pubmed-81266992021-05-18 Metformin Increases Sarcolemma Integrity and Ameliorates Neuromuscular Deficits in a Murine Model of Duchenne Muscular Dystrophy Dong, Xia Hui, Tiankun Chen, Jie Yu, Zheng Ren, Dongyan Zou, Suqi Wang, Shunqi Fei, Erkang Jiao, Huifeng Lai, Xinsheng Front Physiol Physiology Duchenne muscular dystrophy (DMD) is a genetic neuromuscular disease characterized by progressive muscle weakness and wasting. Stimulation of AMP-activated protein kinase (AMPK) has been demonstrated to increase muscle function and protect muscle against damage in dystrophic mice. Metformin is a widely used anti-hyperglycemic drug and has been shown to be an indirect activator of AMPK. Based on these findings, we sought to determine the effects of metformin on neuromuscular deficits in mdx murine model of DMD. In this study, we found metformin treatment increased muscle strength accompanied by elevated twitch and tetanic force of tibialis anterior (TA) muscle in mdx mice. Immunofluorescence and electron microscopy analysis of metformin-treated mdx muscles revealed an improvement in muscle fiber membrane integrity. Electrophysiological studies showed the amplitude of miniature endplate potentials (mEPP) was increased in treated mice, indicating metformin also improved neuromuscular transmission of the mdx mice. Analysis of mRNA and protein levels from muscles of treated mice showed an upregulation of AMPK phosphorylation and dystrophin-glycoprotein complex protein expression. In conclusion, metformin can indeed improve muscle function and diminish neuromuscular deficits in mdx mice, suggesting its potential use as a therapeutic drug in DMD patients. Frontiers Media S.A. 2021-05-03 /pmc/articles/PMC8126699/ /pubmed/34012406 http://dx.doi.org/10.3389/fphys.2021.642908 Text en Copyright © 2021 Dong, Hui, Chen, Yu, Ren, Zou, Wang, Fei, Jiao and Lai. https://creativecommons.org/licenses/by/4.0/This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
spellingShingle Physiology
Dong, Xia
Hui, Tiankun
Chen, Jie
Yu, Zheng
Ren, Dongyan
Zou, Suqi
Wang, Shunqi
Fei, Erkang
Jiao, Huifeng
Lai, Xinsheng
Metformin Increases Sarcolemma Integrity and Ameliorates Neuromuscular Deficits in a Murine Model of Duchenne Muscular Dystrophy
title Metformin Increases Sarcolemma Integrity and Ameliorates Neuromuscular Deficits in a Murine Model of Duchenne Muscular Dystrophy
title_full Metformin Increases Sarcolemma Integrity and Ameliorates Neuromuscular Deficits in a Murine Model of Duchenne Muscular Dystrophy
title_fullStr Metformin Increases Sarcolemma Integrity and Ameliorates Neuromuscular Deficits in a Murine Model of Duchenne Muscular Dystrophy
title_full_unstemmed Metformin Increases Sarcolemma Integrity and Ameliorates Neuromuscular Deficits in a Murine Model of Duchenne Muscular Dystrophy
title_short Metformin Increases Sarcolemma Integrity and Ameliorates Neuromuscular Deficits in a Murine Model of Duchenne Muscular Dystrophy
title_sort metformin increases sarcolemma integrity and ameliorates neuromuscular deficits in a murine model of duchenne muscular dystrophy
topic Physiology
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8126699/
https://www.ncbi.nlm.nih.gov/pubmed/34012406
http://dx.doi.org/10.3389/fphys.2021.642908
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