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Article Abstract
Mutations in the RYR1 gene cause severe myopathies. Mice with an I4895T mutation in the type 1 ryanodine receptor/Ca release channel (RyR1) display muscle weakness and atrophy, but the underlying mechanisms are unclear. Here we show that the I4895T mutation in RyR1 decreases the amplitude of the sarcoplasmic reticulum (SR) Ca transient, resting cytosolic Ca levels, muscle triadin content and calsequestrin (CSQ) localization to the junctional SR, and increases endoplasmic reticulum (ER) stress/unfolded protein response (UPR) and mitochondrial ROS production. Treatment of mice carrying the I4895T mutation with a chemical chaperone, sodium 4-phenylbutyrate (4PBA), reduces ER stress/UPR and improves muscle function, but does not restore SR Ca transients in I4895T fibres to wild type levels, suggesting that decreased SR Ca release is not the major driver of the myopathy. These findings suggest that 4PBA, an FDA-approved drug, has potential as a therapeutic intervention for RyR1 myopathies that are associated with ER stress.
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| http://dx.doi.org/10.1038/ncomms14659 | DOI Listing |
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Article Synopsis
- RyR1 is a type of ryanodine receptor found mainly in brain regions like the cerebellum, hippocampus, and hypothalamus, and is linked to calcium signaling in neurons.
- Researchers found that RyR1 is involved in voltage-induced calcium release (VICaR) in hypothalamic nerve terminals, similar to its function in skeletal muscle.
- In mice with a specific RyR1 mutation associated with a severe human disease, VICaR was absent, indicating that RyR1 not only mediates calcium release but also contributes to a neuronal phenotype related to the myopathy seen in these mice.