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.

RYR-1-Related Diseases International Research Workshop: From Mechanisms to Treatments Pittsburgh, PA, U.S.A., 21-22 July 2022

“…Thus, epigenetic modifying enzymes may constitute a valid therapeutic target for RYR1-RM. Consistent with this, inhibiting DNA methyltransferases and class II histone deacetylases improves muscle function in a mouse model of recessive RYR1-RM [60], providing a proof-of-concept for the pharmacological treatment of patients with CM linked to recessive RYR1 variants. In recently published work, the Zorzato/Treves team investigated the expression of different transcripts, including those encoding epigenetic enzymes, in human muscle biopsies from patients with genetically diverse CMs.…”

Epilepsy-linked kinase CDKL5 phosphorylates voltage-gated calcium channel Cav2.3, altering inactivation kinetics and neuronal excitability

“…Home-cage behaviour and social interaction phenotypes are also common between Cav2.3 phosphomutant and CDKL5 KO mice 46, 71 . The deficits observed in voluntary wheel in Cav2.3 phosphomutants could be indicative of mild hypotonia 82, 83 . Importantly, these phosphomutant mouse phenotypes mirror human clinical manifestations of CDD, arguing that slowed inactivation and enhanced cholinergic modulation of unphosphorylated Cav2.3 may contribute to these symptoms.…”

“…Cav2.3 S15A mice recapitulate the reduced home-cage locomotion behaviour in CDKL5 KO mice 48,73 . The deficits observed in voluntary wheel in Cav2.3 phosphomutants could be indicative of mild hypotonia 86,87 . Finally, reduced social interaction in Cav2.3 phosphomutant mice was also observed in CDKL5 KO mice 15,48,73 and inhibitory neuron specific deletion of CDKL5 88 .…”

Mutations in proteins involved in E-C coupling and SOCE and congenital myopathies

“…The reason for the selective effect of the homozygous A4329D mutation in slow-twitch fibers is not known; the authors suggested that a different epigenetic regulation of fast- versus slow-twitch muscle fibers may account, at least in part, for these differences ( Elbaz et al, 2020 ). Indeed, an increase in histone deacetylase (HDAC) was observed in soleus muscle of Ryr1 A4329D mice and, interestingly, in muscles from patients carrying recessive RYR1 mutations ( Zhou et al, 2006 ; Rokach et al, 2015 ; Ruiz et al, 2022 ). Although the correlation between expression of mutant RYR1 channels and epigenetic changes is not clear, the use of an inhibitor of HDAC and DNA methylase significantly improved muscle strength and RYR1 expression ( Ruiz et al, 2022 ).…”

“…Indeed, an increase in histone deacetylase (HDAC) was observed in soleus muscle of Ryr1 A4329D mice and, interestingly, in muscles from patients carrying recessive RYR1 mutations ( Zhou et al, 2006 ; Rokach et al, 2015 ; Ruiz et al, 2022 ). Although the correlation between expression of mutant RYR1 channels and epigenetic changes is not clear, the use of an inhibitor of HDAC and DNA methylase significantly improved muscle strength and RYR1 expression ( Ruiz et al, 2022 ).…”