4.8 Article

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

Journal

ELIFE
Volume 11, Issue -, Pages -

Publisher

eLIFE SCIENCES PUBL LTD
DOI: 10.7554/eLife.73718

Keywords

ryanodine receptor mutations; congenital myopathy; treatment; muscle function; epigenetic enzymes; Mouse

Categories

Funding

  1. Swiss National Science Foundation [SNF 310030_184765]
  2. Swiss Muscle Foundation FRSM
  3. NeRAB Susan Treves
  4. RYR1 Foundation Francesco Zorzato
  5. Swiss National Science Foundation (SNF) [310030_184765] Funding Source: Swiss National Science Foundation (SNF)

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Currently, there are no therapies available for patients with congenital myopathies, which greatly affects their quality of life. However, a recent study found that targeting epigenetic enzymes with drugs can improve muscle strength and ultrastructure in mice with certain RYR1 gene mutations. This provides a proof of concept for potential pharmacological treatment of patients with congenital myopathies linked to recessive RYR1 mutations.
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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