Abstract
Mutations in the RYR1 gene cause severe myopathies. Mice with an I4895T mutation in the type 1 ryanodine receptor/Ca2+ 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) Ca2+ transient, resting cytosolic Ca2+ 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 Ca2+ transients in I4895T fibres to wild type levels, suggesting that decreased SR Ca2+ 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.
Highlights
Mutations in the RYR1 gene cause severe myopathies
We have shown that a mutation in Ryr[1] that leads to the replacement of tyrosine with a serine at amino acid 524 in RyR1 (Y522S in humans, Y524S in mice), which cause both malignant hyperthermia and myopathy with cores, increases heat sensitivity, temperature-dependent sarcoplasmic reticulum (SR) Ca2þ leak, mitochondrial damage and oxidative/nitrosative stress[5]
In the present study we demonstrate that persistent endoplasmic reticulum (ER) stress/unfolded protein response (UPR) and excessive mitochondrial reactive oxygen species (ROS) production contribute to muscle weakness and atrophy in mice with the I4895T mutation in RyR1 and that both the weakness and the atrophy are reversed by the treatment of these IT mice with a chemical chaperone, 4-phenylbutyrate (4PBA)
Summary
Mutations in the RYR1 gene cause severe myopathies. Mice with an I4895T mutation in the type 1 ryanodine receptor/Ca2þ release channel (RyR1) display muscle weakness and atrophy, but the underlying mechanisms are unclear. 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 Ca2þ transients in I4895T fibres to wild type levels, suggesting that decreased SR Ca2þ 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. In the present study we demonstrate that persistent endoplasmic reticulum (ER) stress/UPR and excessive mitochondrial reactive oxygen species (ROS) production contribute to muscle weakness and atrophy in mice with the I4895T mutation in RyR1 and that both the weakness and the atrophy are reversed by the treatment of these IT mice with a chemical chaperone, 4-phenylbutyrate (4PBA)
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