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Net39 protects muscle nuclei from mechanical stress during the pathogenesis of Emery-Dreifuss muscular dystrophy

Mutations in genes encoding nuclear envelope proteins lead to diseases known as nuclear envelopathies, characterized by skeletal muscle and heart abnormalities, such as Emery-Dreifuss muscular dystrophy (EDMD). The tissue-specific role of the nuclear envelope in the etiology of these diseases has no...

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Autores principales: Zhang, Yichi, Ramirez-Martinez, Andres, Chen, Kenian, McAnally, John R., Cai, Chunyu, Durbacz, Mateusz Z., Chemello, Francesco, Wang, Zhaoning, Xu, Lin, Bassel-Duby, Rhonda, Liu, Ning, Olson, Eric N.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: American Society for Clinical Investigation 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10313361/
https://www.ncbi.nlm.nih.gov/pubmed/37395273
http://dx.doi.org/10.1172/JCI163333
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author Zhang, Yichi
Ramirez-Martinez, Andres
Chen, Kenian
McAnally, John R.
Cai, Chunyu
Durbacz, Mateusz Z.
Chemello, Francesco
Wang, Zhaoning
Xu, Lin
Bassel-Duby, Rhonda
Liu, Ning
Olson, Eric N.
author_facet Zhang, Yichi
Ramirez-Martinez, Andres
Chen, Kenian
McAnally, John R.
Cai, Chunyu
Durbacz, Mateusz Z.
Chemello, Francesco
Wang, Zhaoning
Xu, Lin
Bassel-Duby, Rhonda
Liu, Ning
Olson, Eric N.
author_sort Zhang, Yichi
collection PubMed
description Mutations in genes encoding nuclear envelope proteins lead to diseases known as nuclear envelopathies, characterized by skeletal muscle and heart abnormalities, such as Emery-Dreifuss muscular dystrophy (EDMD). The tissue-specific role of the nuclear envelope in the etiology of these diseases has not been extensively explored. We previously showed that global deletion of the muscle-specific nuclear envelope protein NET39 in mice leads to neonatal lethality due to skeletal muscle dysfunction. To study the potential role of the Net39 gene in adulthood, we generated a muscle-specific conditional knockout (cKO) of Net39 in mice. cKO mice recapitulated key skeletal muscle features of EDMD, including muscle wasting, impaired muscle contractility, abnormal myonuclear morphology, and DNA damage. The loss of Net39 rendered myoblasts hypersensitive to mechanical stretch, resulting in stretch-induced DNA damage. Net39 was downregulated in a mouse model of congenital myopathy, and restoration of Net39 expression through AAV gene delivery extended life span and ameliorated muscle abnormalities. These findings establish NET39 as a direct contributor to the pathogenesis of EDMD that acts by protecting against mechanical stress and DNA damage.
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spelling pubmed-103133612023-07-03 Net39 protects muscle nuclei from mechanical stress during the pathogenesis of Emery-Dreifuss muscular dystrophy Zhang, Yichi Ramirez-Martinez, Andres Chen, Kenian McAnally, John R. Cai, Chunyu Durbacz, Mateusz Z. Chemello, Francesco Wang, Zhaoning Xu, Lin Bassel-Duby, Rhonda Liu, Ning Olson, Eric N. J Clin Invest Research Article Mutations in genes encoding nuclear envelope proteins lead to diseases known as nuclear envelopathies, characterized by skeletal muscle and heart abnormalities, such as Emery-Dreifuss muscular dystrophy (EDMD). The tissue-specific role of the nuclear envelope in the etiology of these diseases has not been extensively explored. We previously showed that global deletion of the muscle-specific nuclear envelope protein NET39 in mice leads to neonatal lethality due to skeletal muscle dysfunction. To study the potential role of the Net39 gene in adulthood, we generated a muscle-specific conditional knockout (cKO) of Net39 in mice. cKO mice recapitulated key skeletal muscle features of EDMD, including muscle wasting, impaired muscle contractility, abnormal myonuclear morphology, and DNA damage. The loss of Net39 rendered myoblasts hypersensitive to mechanical stretch, resulting in stretch-induced DNA damage. Net39 was downregulated in a mouse model of congenital myopathy, and restoration of Net39 expression through AAV gene delivery extended life span and ameliorated muscle abnormalities. These findings establish NET39 as a direct contributor to the pathogenesis of EDMD that acts by protecting against mechanical stress and DNA damage. American Society for Clinical Investigation 2023-07-03 /pmc/articles/PMC10313361/ /pubmed/37395273 http://dx.doi.org/10.1172/JCI163333 Text en © 2023 Zhang et al. https://creativecommons.org/licenses/by/4.0/This work is licensed under the Creative Commons Attribution 4.0 International License. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) .
spellingShingle Research Article
Zhang, Yichi
Ramirez-Martinez, Andres
Chen, Kenian
McAnally, John R.
Cai, Chunyu
Durbacz, Mateusz Z.
Chemello, Francesco
Wang, Zhaoning
Xu, Lin
Bassel-Duby, Rhonda
Liu, Ning
Olson, Eric N.
Net39 protects muscle nuclei from mechanical stress during the pathogenesis of Emery-Dreifuss muscular dystrophy
title Net39 protects muscle nuclei from mechanical stress during the pathogenesis of Emery-Dreifuss muscular dystrophy
title_full Net39 protects muscle nuclei from mechanical stress during the pathogenesis of Emery-Dreifuss muscular dystrophy
title_fullStr Net39 protects muscle nuclei from mechanical stress during the pathogenesis of Emery-Dreifuss muscular dystrophy
title_full_unstemmed Net39 protects muscle nuclei from mechanical stress during the pathogenesis of Emery-Dreifuss muscular dystrophy
title_short Net39 protects muscle nuclei from mechanical stress during the pathogenesis of Emery-Dreifuss muscular dystrophy
title_sort net39 protects muscle nuclei from mechanical stress during the pathogenesis of emery-dreifuss muscular dystrophy
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10313361/
https://www.ncbi.nlm.nih.gov/pubmed/37395273
http://dx.doi.org/10.1172/JCI163333
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