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

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.

Metrics

  • 1,572
    views
  • 220
    downloads
  • 11
    citations

Views, downloads and citations are aggregated across all versions of this paper published by eLife.

Download links

A two-part list of links to download the article, or parts of the article, in various formats.

Downloads (link to download the article as PDF)

Open citations (links to open the citations from this article in various online reference manager services)

Cite this article (links to download the citations from this article in formats compatible with various reference manager tools)

  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

Share this article

https://doi.org/10.7554/eLife.73718

Further reading

    1. Computational and Systems Biology
    2. Medicine
    Xin Zhou, Zhinuo Jenny Wang ... Blanca Rodriguez
    Research Article

    Sudden death after myocardial infarction (MI) is associated with electrophysiological heterogeneities and ionic current remodelling. Low ejection fraction (EF) is used in risk stratification, but its mechanistic links with pro-arrhythmic heterogeneities are unknown. We aim to provide mechanistic explanations of clinical phenotypes in acute and chronic MI, from ionic current remodelling to ECG and EF, using human electromechanical modelling and simulation to augment experimental and clinical investigations. A human ventricular electromechanical modelling and simulation framework is constructed and validated with rich experimental and clinical datasets, incorporating varying degrees of ionic current remodelling as reported in literature. In acute MI, T-wave inversion and Brugada phenocopy were explained by conduction abnormality and local action potential prolongation in the border zone. In chronic MI, upright tall T-waves highlight large repolarisation dispersion between the border and remote zones, which promoted ectopic propagation at fast pacing. Post-MI EF at resting heart rate was not sensitive to the extent of repolarisation heterogeneity and the risk of repolarisation abnormalities at fast pacing. T-wave and QT abnormalities are better indicators of repolarisation heterogeneities than EF in post-MI.

    1. Medicine
    2. Microbiology and Infectious Disease
    Berit Siedentop, Viacheslav N Kachalov ... Sebastian Bonhoeffer
    Research Article

    Background:

    Under which conditions antibiotic combination therapy decelerates rather than accelerates resistance evolution is not well understood. We examined the effect of combining antibiotics on within-patient resistance development across various bacterial pathogens and antibiotics.

    Methods:

    We searched CENTRAL, EMBASE, and PubMed for (quasi)-randomised controlled trials (RCTs) published from database inception to 24 November 2022. Trials comparing antibiotic treatments with different numbers of antibiotics were included. Patients were considered to have acquired resistance if, at the follow-up culture, a resistant bacterium (as defined by the study authors) was detected that had not been present in the baseline culture. We combined results using a random effects model and performed meta-regression and stratified analyses. The trials’ risk of bias was assessed with the Cochrane tool.

    Results:

    42 trials were eligible and 29, including 5054 patients, qualified for statistical analysis. In most trials, resistance development was not the primary outcome and studies lacked power. The combined odds ratio for the acquisition of resistance comparing the group with the higher number of antibiotics with the comparison group was 1.23 (95% CI 0.68–2.25), with substantial between-study heterogeneity (I2=77%). We identified tentative evidence for potential beneficial or detrimental effects of antibiotic combination therapy for specific pathogens or medical conditions.

    Conclusions:

    The evidence for combining a higher number of antibiotics compared to fewer from RCTs is scarce and overall compatible with both benefit or harm. Trials powered to detect differences in resistance development or well-designed observational studies are required to clarify the impact of combination therapy on resistance.

    Funding:

    Support from the Swiss National Science Foundation (grant 310030B_176401 (SB, BS, CW), grant 32FP30-174281 (ME), grant 324730_207957 (RDK)) and from the National Institute of Allergy and Infectious Diseases (NIAID, cooperative agreement AI069924 (ME)) is gratefully acknowledged.