Improvement of muscle strength in a mouse model for congenital myopathy treated with HDAC and DNA methyltransferase inhibitors
Improvement of muscle strength in a mouse model for congenital myopathy treated with HDAC and DNA methyltransferase inhibitors
Abstract 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 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 de-acetylases 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 de-acetylases. 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.
Benucci Sofia、Duthaler Urs、Bachmann Christoph、Franchini Martina、Treves Susan、Zorzato Francesco、Pietrangelo Laura、Noreen Faiza、Protasi Feliciano、Ruiz Alexis
Neuromuscular Research Group, Department of Biomedicine, Basel University HospitalDivision of Clinical Pharmacology & Toxicology, Department of Biomedicine, University and University Hospital BaselNeuromuscular Research Group, Department of Biomedicine, Basel University HospitalNeuromuscular Research Group, Department of Biomedicine, Basel University HospitalNeuromuscular Research Group, Department of Biomedicine, Basel University Hospital||Department of Life Science and Biotechnology, University of FerraraNeuromuscular Research Group, Department of Biomedicine, Basel University Hospital||Department of Life Science and Biotechnology, University of FerraraCAST, Center for Advanced Studies and Technology & DMSI, Dept. of Neuroscience, Imaging and Clinical Sciences, Univ. G. d?ˉAnnunzioGenome plasticity group, Department of Biomedicine, University of BaselCAST, Center for Advanced Studies and Technology & DMSI, Dept. of Neuroscience, Imaging and Clinical Sciences, Univ. G. d?ˉAnnunzioNeuromuscular Research Group, Department of Biomedicine, Basel University Hospital
基础医学药学分子生物学
Benucci Sofia,Duthaler Urs,Bachmann Christoph,Franchini Martina,Treves Susan,Zorzato Francesco,Pietrangelo Laura,Noreen Faiza,Protasi Feliciano,Ruiz Alexis.Improvement of muscle strength in a mouse model for congenital myopathy treated with HDAC and DNA methyltransferase inhibitors[EB/OL].(2025-03-28)[2025-05-23].https://www.biorxiv.org/content/10.1101/2021.11.09.467894.点此复制
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