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 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.
Highlights
Skeletal muscle contraction is initiated by a massive release of Ca2+ from the sarcoplasmic reticulum (SR) via the opening of the ryanodine receptor 1 (RyR1), a calcium release channel, which is localized in the SR terminal cisternae [1-3]
After intraperitoneal injection of 25 mg/kg body weight of 99 TMP269 dissolved in Polyethylenglycol 300 (PEG300) (500 μl/Kg) and N-Methyl-2-pyrrolidone (NMP) (250 μL/Kg), blood and/or skeletal muscles were collected at different time points and the content of TMP269 was quantified by liquid chromatography tandem mass spectrometry [21]
Administration of TMP269+5-Aza-2109 deoxycytidine (5-Aza) for 15 weeks increases the acetylation of Lys residues (Appendix 2-figure 2A and Appendix 2-figure 2 source data 1-5) and of H3K9 (Appendix 2-figure 2B, 2D and Appendix 2-figure source data 1-5) in total homogenates from flexor digitorum brevis (FDB) fibers isolated from wild type (WT) and double heterozygous (dHT) mice, compared to that observed in fibers from vehicle treated WT and dHT mice
Summary
Skeletal muscle contraction is initiated by a massive release of Ca2+ from the sarcoplasmic reticulum (SR) via the opening of the ryanodine receptor 1 (RyR1), a calcium release channel, which is localized in the SR terminal cisternae [1-3]. The signal causing the opening of the RyR1 is the depolarization of the sarcolemmal membrane, which is sensed by voltage-dependent L49 type Ca2+ channels (dihydropyridine receptor, DHPR) located in invaginations of the sarcolemma referred to as transverse tubules (TTs)(1, 4). The second class of RYR1 mutations (dominant, CCD-associated) results in leaky channels leading to depletion of Ca2+ from SR stores [7, 8]. A third class of RYR1 mutations linked to CCD causes EC uncoupling, whereby activation of the voltage sensor Cav1.1 is unable to cause release of Ca2+ from the SR [10]. The fourth class comprises recessive mutations, which are accompanied by a decreased content of mutant RyR1 channels on SR membranes [11-14]
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