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Updated: May 28, 2025
Functional Characterization of Endogenously Expressed Human RYR1 Variants
Published on: June 9, 2021
5-aza-2-deoxycytidine improves skeletal muscle function in a mouse model for recessive RYR1-related congenital
Alexis Ruiz1, Faiza Noreen2, Hervé Meier1
1Neuromuscular Research Group, Departments of Neurology and Biomedicine, Basel University Hospital, Hebelstrasse 20, 4031 Basel, Switzerland.
Abstract:
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.
Insights
This study shows that 5-aza-2'-deoxycytidine can improve muscle function in a mouse model of RYR1-related congenital myopathies. This finding offers hope for a new pharmacological therapy for patients with this rare muscle disorder.
Area of Science:
- Genetics and Molecular Biology
- Neurology
- Pharmacology
Background:
- RYR1-related congenital myopathies are severe genetic muscle disorders with no current pharmacological treatments.
- The most severe forms result from compound heterozygous mutations in RYR1, leading to reduced protein levels and altered muscle composition.
- Muscle weakness significantly impacts patient quality of life.
Purpose of the Study:
- To investigate the therapeutic potential of 5-aza-2 ahydrogen-deoxycytidine in a pre-clinical model of RYR1-related congenital myopathies.
- To evaluate the drug's effects on muscle strength, calcium homeostasis, and muscle proteome.
- To provide proof of concept for a potential pharmacological treatment for recessive RYR1 myopathies.
Main Methods:
- Treatment of a mouse model (dHT mice) with compound heterozygous RYR1 pathogenic variants (p.Q1970fsX16 + p.A4329D) for 15 weeks.
- Administration of 5-aza-2 ahydrogen-deoxycytidine at a dose of 0.05 mg/kg.
- Assessment of muscle strength, calcium handling, and muscle proteomic profiles.
Main Results:
- Drug treatment significantly improved muscle strength in dHT mice.
- Enhanced calcium homeostasis was observed following treatment.
- Beneficial effects were particularly pronounced in fast-twitch muscles, which are typically affected early in the disease.
- Muscle proteome analysis indicated positive biochemical changes.
Conclusions:
- 5-aza-2 ahydrogen-deoxycytidine demonstrates therapeutic potential for recessive RYR1-related congenital myopathies.
- The drug's efficacy in improving muscle function and biochemistry supports its consideration for clinical trials.
- This study provides a strong foundation for developing a phase 1/2 clinical trial for affected patients.
