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Improvement of muscle strength in a mouse model for congenital myopathy treated with HDAC and DNA methyltransferase inhibitors

To date there are no therapies for patients with congenital myopathies, muscle disorders causing poor quality of life of affected individuals. In approximately 30% of the cases, patients with congenital myopathies carry either dominant or recessive mutations in the ryanodine receptor 1 (RYR1) gene;...

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Autores principales: Ruiz, Alexis, Benucci, Sofia, Duthaler, Urs, Bachmann, Christoph, Franchini, Martina, Noreen, Faiza, Pietrangelo, Laura, Protasi, Feliciano, Treves, Susan, Zorzato, Francesco
Formato: Online Artículo Texto
Lenguaje:English
Publicado: eLife Sciences Publications, Ltd 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8956288/
https://www.ncbi.nlm.nih.gov/pubmed/35238775
http://dx.doi.org/10.7554/eLife.73718
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author Ruiz, Alexis
Benucci, Sofia
Duthaler, Urs
Bachmann, Christoph
Franchini, Martina
Noreen, Faiza
Pietrangelo, Laura
Protasi, Feliciano
Treves, Susan
Zorzato, Francesco
author_facet Ruiz, Alexis
Benucci, Sofia
Duthaler, Urs
Bachmann, Christoph
Franchini, Martina
Noreen, Faiza
Pietrangelo, Laura
Protasi, Feliciano
Treves, Susan
Zorzato, Francesco
author_sort Ruiz, Alexis
collection PubMed
description To date there are no therapies for patients with congenital myopathies, muscle disorders causing poor quality of life of affected individuals. In approximately 30% of the cases, patients with congenital myopathies carry either dominant or recessive mutations in the ryanodine receptor 1 (RYR1) gene; recessive RYR1 mutations are accompanied by reduction of RyR1 expression and content in skeletal muscles and are associated with fiber hypotrophy and muscle weakness. Importantly, muscles of patients with recessive RYR1 mutations exhibit increased content of class II histone deacetylases and of DNA genomic methylation. We recently created a mouse model knocked-in for the p.Q1970fsX16+ p.A4329D RyR1 mutations, which are isogenic to those carried by a severely affected child suffering from a recessive form of RyR1-related multi-mini core disease. The phenotype of the RyR1 mutant mice recapitulates many aspects of the clinical picture of patients carrying recessive RYR1 mutations. We treated the compound heterozygous mice with a combination of two drugs targeting DNA methylases and class II histone deacetylases. Here, we show that treatment of the mutant mice with drugs targeting epigenetic enzymes improves muscle strength, RyR1 protein content, and muscle ultrastructure. This study provides proof of concept for the pharmacological treatment of patients with congenital myopathies linked to recessive RYR1 mutations.
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spelling pubmed-89562882022-03-26 Improvement of muscle strength in a mouse model for congenital myopathy treated with HDAC and DNA methyltransferase inhibitors Ruiz, Alexis Benucci, Sofia Duthaler, Urs Bachmann, Christoph Franchini, Martina Noreen, Faiza Pietrangelo, Laura Protasi, Feliciano Treves, Susan Zorzato, Francesco eLife Medicine To date there are no therapies for patients with congenital myopathies, muscle disorders causing poor quality of life of affected individuals. In approximately 30% of the cases, patients with congenital myopathies carry either dominant or recessive mutations in the ryanodine receptor 1 (RYR1) gene; recessive RYR1 mutations are accompanied by reduction of RyR1 expression and content in skeletal muscles and are associated with fiber hypotrophy and muscle weakness. Importantly, muscles of patients with recessive RYR1 mutations exhibit increased content of class II histone deacetylases and of DNA genomic methylation. We recently created a mouse model knocked-in for the p.Q1970fsX16+ p.A4329D RyR1 mutations, which are isogenic to those carried by a severely affected child suffering from a recessive form of RyR1-related multi-mini core disease. The phenotype of the RyR1 mutant mice recapitulates many aspects of the clinical picture of patients carrying recessive RYR1 mutations. We treated the compound heterozygous mice with a combination of two drugs targeting DNA methylases and class II histone deacetylases. Here, we show that treatment of the mutant mice with drugs targeting epigenetic enzymes improves muscle strength, RyR1 protein content, and muscle ultrastructure. This study provides proof of concept for the pharmacological treatment of patients with congenital myopathies linked to recessive RYR1 mutations. eLife Sciences Publications, Ltd 2022-03-03 /pmc/articles/PMC8956288/ /pubmed/35238775 http://dx.doi.org/10.7554/eLife.73718 Text en © 2022, Ruiz et al https://creativecommons.org/licenses/by/4.0/This article is distributed under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0/) , which permits unrestricted use and redistribution provided that the original author and source are credited.
spellingShingle Medicine
Ruiz, Alexis
Benucci, Sofia
Duthaler, Urs
Bachmann, Christoph
Franchini, Martina
Noreen, Faiza
Pietrangelo, Laura
Protasi, Feliciano
Treves, Susan
Zorzato, Francesco
Improvement of muscle strength in a mouse model for congenital myopathy treated with HDAC and DNA methyltransferase inhibitors
title Improvement of muscle strength in a mouse model for congenital myopathy treated with HDAC and DNA methyltransferase inhibitors
title_full Improvement of muscle strength in a mouse model for congenital myopathy treated with HDAC and DNA methyltransferase inhibitors
title_fullStr Improvement of muscle strength in a mouse model for congenital myopathy treated with HDAC and DNA methyltransferase inhibitors
title_full_unstemmed Improvement of muscle strength in a mouse model for congenital myopathy treated with HDAC and DNA methyltransferase inhibitors
title_short Improvement of muscle strength in a mouse model for congenital myopathy treated with HDAC and DNA methyltransferase inhibitors
title_sort improvement of muscle strength in a mouse model for congenital myopathy treated with hdac and dna methyltransferase inhibitors
topic Medicine
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8956288/
https://www.ncbi.nlm.nih.gov/pubmed/35238775
http://dx.doi.org/10.7554/eLife.73718
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