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

ABSTRACT: RYR1 congenital myopathies are rare disorders severely impacting muscle function and impairing the quality of life of patients and their families, yet to date, no pharmacological therapies are available to treat the severe muscle weakness of affected patients. The recessive forms of RYR1-related congenital myopathies caused by nonsense/ frameshift mutations in one allele and a missense mutation in the other allele, resulting in the homozygous and reduced expression of the missense mutation are the most severe forms. They are often accompanied by a reduction of RyR1 protein and significant changes in the biochemical composition of muscles. Using a mouse model carrying the RyR1 p.Q1970fsX16+p.A4329D compound heterozygous mutations (dHT mice),we performed a pre-clinical study and injected mice for 15 weeks with 0.05 mg/kg of the FDA approved drug 5-aza-2-deoxycytidine which targets the epigenetic enzymes DNA methyltransferases. We evaluated muscle strength, calcium homeostasis and proteome and report that drug treatment improves all investigated muscle function in drug treated 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 congenital myopathies linked to recessive RYR1 mutations, leading the path to a phase 1 clinical study by repurposing an FDA approved drug.

ORGANISM(S): Mus musculus

PROVIDER: GSE277979 | GEO | 2025/04/07

REPOSITORIES: GEO

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Project description:<p>Severe myopathic events occur in 0.1-0.5% of patients taking statins. Although genetic association studies have identified some possibly associated gene loci, these have not been reproducible in additional studies with independent patient cohorts. A more reasonable explanation for susceptibility to statin-induced myopathy is the presence of rare pathogenic variants in genes important for skeletal muscle structure and function. In support of this, we have previously reported an increased incidence of pathogenic variants in genes causing metabolic myopathies in patients with statin-induced myopathy (<a href="https://www.ncbi.nlm.nih.gov/pubmed/16671104">Vladutiu et al.</a>,2006). We also reported a patient with statin myopathy who had an <i>RYR1</i> variant known to be causative of malignant hyperthermia susceptibility (MHS) (<a href="https://www.ncbi.nlm.nih.gov/pubmed/21795085">Vladutiu et al.</a>, 2011). There are a number of genes associated with metabolic myopathies triggered by various factors such as extreme exercise, fasting, extremes in temperature, viral infection and exposure to volatile anesthetics. In addition, many of the genes causing congenital myopathies, myofibrillar myopathies and muscular dystrophies have overlapping phenotypes with these genes. We propose that statins act as an additional trigger inducing myopathic symptoms and many patients with severe statin-induced myopathy have causative genetic variants within similar genes associated with MHS and congenital myopathy. We have analyzed the resultant data using a disease model in which rare pathogenic variants, possibly within multiple genes, are causative of statin-induced myopathy. In this study, we have identified potentially causative genetic variants in greater than 50% of the statin-induced myopathy cases and in particular, rare and possibly pathogenic in the RYR1 and CACNA1S genes were present in 25% of the patient samples studied. Vladutiu, G. D., Simmons, Z., Isackson, P.J., Tarnopolsky, M., Peltier, W.L., Barboi, A.C., Sripathi, N., Wortmann, R.L., Phillips, P.S., (<a href="https://www.ncbi.nlm.nih.gov/pubmed/16671104">2006</a>). "Genetic risk factors associated with lipid-lowering drug-induced myopathies." Muscle Nerve 34: 153-162. Vladutiu, G. D., Isackson, P.J., Kaufman, K., Harley, J.B., Cobb, B., Christopher-Stine, L., Wortmann, R.L, (<a href="https://www.ncbi.nlm.nih.gov/pubmed/21795085">2011</a>). "Genetic risk for malignant hyperthermia in non-anesthesia-induced myopathies." Mol Genet Metab 104: 167-173. </p>

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

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