5-aza-2-deoxycytidine improves skeletal muscle function in a mouse model for recessive RYR1-related congenital myopathy.

RYR1-related congenital myopathies are rare disorders that severely impair muscle function and the quality of life of patients and their families. To date no pharmacological therapies are available to treat the severe muscle weakness of affected patients. The most severe forms of RYR1-related congenital myopathies are caused by compound heterozygous mutations (nonsense/frameshift in one allele and a missense mutation in the other), leading to reduced RyR1 protein levels and altered biochemical composition of muscles. In this pre-clinical study, we treated a mouse model carrying the RyR1 p.Q1970fsX16 + p.A4329D compound heterozygous pathogenic variants (dHT mice) for 15 weeks with 0.05 mg/kg 5-aza-2'-deoxycytidine, an FDA-approved drug targeting DNA methyltransferases. We evaluated muscle strength, calcium homeostasis and muscle proteome and report that drug treatment improves all investigated parameters in dHT mice. Importantly, the beneficial effects were particularly significant in fast twitch muscles which are the first muscles to be impaired in patients. In conclusion, this study provides proof of concept for the pharmacological treatment of patients with recessive RYR1-related congenital myopathies with the FDA approved 5-aza-2'-deoxycytidine, supporting its use in a phase 1/2 clinical trial.