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

  1. Alexis Ruiz
  2. Sofia Benucci
  3. Urs Duthaler
  4. Christoph Bachmann
  5. Martina Franchini
  6. Faiza Noreen
  7. Laura Pietrangelo
  8. Feliciano Protasi
  9. Susan Treves
  10. Francesco Zorzato  Is a corresponding author
  1. Basel University Hospital, Switzerland
  2. University of Basel, Switzerland
  3. University G d' Annunzio of Chieti, Italy

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.

Data availability

All data, code, and materials used in the analysis are available in some form to any researcher for purposes of reproducing or extending the analysis. There are no restrictions on materials, such as materials transfer agreements (MTAs). All data are available in the main text or the supplementary materials.

Article and author information

Author details

  1. Alexis Ruiz

    Department of Biomedicine, Basel University Hospital, Basel, Switzerland
    Competing interests
    The authors declare that no competing interests exist.
  2. Sofia Benucci

    Department of Biomedicine, Basel University Hospital, Basel, Switzerland
    Competing interests
    The authors declare that no competing interests exist.
  3. Urs Duthaler

    Department of Biomedicine, Basel University Hospital, Basel, Switzerland
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-7811-3932
  4. Christoph Bachmann

    Department of Biomedicine, Basel University Hospital, Basel, Switzerland
    Competing interests
    The authors declare that no competing interests exist.
  5. Martina Franchini

    Department of Biomedicine, Basel University Hospital, Basel, Switzerland
    Competing interests
    The authors declare that no competing interests exist.
  6. Faiza Noreen

    Department of Biomedicine, University of Basel, Basel, Switzerland
    Competing interests
    The authors declare that no competing interests exist.
  7. Laura Pietrangelo

    Department of Neuroscience, Imaging and Clinical Science, University G d' Annunzio of Chieti, Chieti, Italy
    Competing interests
    The authors declare that no competing interests exist.
  8. Feliciano Protasi

    Department of Neuroscience, Imaging and Clinical Science, University G d' Annunzio of Chieti, Chieti, Italy
    Competing interests
    The authors declare that no competing interests exist.
  9. Susan Treves

    Department of Biomedicine, Basel University Hospital, Basel, Switzerland
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-0007-9631
  10. Francesco Zorzato

    Department of Biomedicine, Basel University Hospital, Basel, Switzerland
    For correspondence
    fzorzato@usb.ch
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-8469-7065

Funding

Swiss National Science Foundation (SNF 310030_184765)

  • Susan Treves

Swiss Muscle Foundation (FRSMM)

  • Francesco Zorzato

NeRAB

  • Susan Treves

RYR1 Foundation

  • Francesco Zorzato

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Ethics

Animal experimentation: This study was performed in strict accordance with the recommendations of the Basel Stadt Kantonal authorities. All animals were handled according to approved institutional animal care and use committee. The protocols were approved by the Kantonal Veterinary Authorities included in Licence permits numbers 1728 and 2950

Reviewing Editor

  1. Christopher L-H Huang, University of Cambridge, United Kingdom

Publication history

  1. Received: September 8, 2021
  2. Preprint posted: November 9, 2021 (view preprint)
  3. Accepted: February 18, 2022
  4. Accepted Manuscript published: March 3, 2022 (version 1)
  5. Version of Record published: March 25, 2022 (version 2)

Copyright

© 2022, Ruiz et al.

This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.

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  1. Alexis Ruiz
  2. Sofia Benucci
  3. Urs Duthaler
  4. Christoph Bachmann
  5. Martina Franchini
  6. Faiza Noreen
  7. Laura Pietrangelo
  8. Feliciano Protasi
  9. Susan Treves
  10. Francesco Zorzato
(2022)
Improvement of muscle strength in a mouse model for congenital myopathy treated with HDAC and DNA methyltransferase inhibitors
eLife 11:e73718.
https://doi.org/10.7554/eLife.73718

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