Improvement of muscle strength in a mouse model for congenital myopathy treated with HDAC and DNA methyltransferase inhibitors
- Basel University Hospital, Switzerland
- University of Basel, Switzerland
- 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
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.
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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
Further reading
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Background:
Post-endoscopic retrograde cholangiopancreatography (ERCP) pancreatitis (PEP) is a severe and deadly adverse event following ERCP. The ideal method for predicting PEP risk before ERCP has yet to be identified. We aimed to establish a simple PEP risk score model (SuPER model: Support for PEP Reduction) that can be applied before ERCP.
Methods:
This multicenter study enrolled 2074 patients who underwent ERCP. Among them, 1037 patients each were randomly assigned to the development and validation cohorts. In the development cohort, the risk score model for predicting PEP was established via logistic regression analysis. In the validation cohort, the performance of the model was assessed.
Results:
In the development cohort, five PEP risk factors that could be identified before ERCP were extracted and assigned weights according to their respective regression coefficients: –2 points for pancreatic calcification, 1 point for female sex, and 2 points for intraductal papillary mucinous neoplasm, a native papilla of Vater, or the pancreatic duct procedures (treated as ‘planned pancreatic duct procedures’ for calculating the score before ERCP). The PEP occurrence rate was 0% among low-risk patients (≤0 points), 5.5% among moderate-risk patients (1–3 points), and 20.2% among high-risk patients (4–7 points). In the validation cohort, the C statistic of the risk score model was 0.71 (95% CI 0.64–0.78), which was considered acceptable. The PEP risk classification (low, moderate, and high) was a significant predictive factor for PEP that was independent of intraprocedural PEP risk factors (precut sphincterotomy and inadvertent pancreatic duct cannulation) (OR 4.2, 95% CI 2.8–6.3; p<0.01).
Conclusions:
The PEP risk score allows an estimation of the risk of PEP prior to ERCP, regardless of whether the patient has undergone pancreatic duct procedures. This simple risk model, consisting of only five items, may aid in predicting and explaining the risk of PEP before ERCP and in preventing PEP by allowing selection of the appropriate expert endoscopist and useful PEP prophylaxes.
Funding:
No external funding was received for this work.
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