A chemical chaperone improves muscle function in mice with a RyR1 mutation

Chang Seok Lee, Amy D. Hanna, Hui Wang, Adan Dagnino-Acosta, Aditya D. Joshi, Mark Knoblauch, Yan Xia, Dimitra K. Georgiou, Jianjun Xu, Cheng Long, Hisayuki Amano, Corey Reynolds, Keke Dong, John C. Martin, William R. Lagor, George G. Rodney, Ergun Sahin, Caroline Sewry and Susan L. Hamilton ()
Additional contact information
Chang Seok Lee: Baylor College of Medicine
Amy D. Hanna: Baylor College of Medicine
Hui Wang: Baylor College of Medicine
Adan Dagnino-Acosta: Baylor College of Medicine
Aditya D. Joshi: Baylor College of Medicine
Mark Knoblauch: Baylor College of Medicine
Yan Xia: Baylor College of Medicine
Dimitra K. Georgiou: Baylor College of Medicine
Jianjun Xu: Baylor College of Medicine
Cheng Long: Baylor College of Medicine
Hisayuki Amano: Baylor College of Medicine
Corey Reynolds: Baylor College of Medicine
Keke Dong: Baylor College of Medicine
John C. Martin: Baylor College of Medicine
William R. Lagor: Baylor College of Medicine
George G. Rodney: Baylor College of Medicine
Ergun Sahin: Baylor College of Medicine
Caroline Sewry: Dubowitz Neuromuscular Centre, UCL Institute of Child Health and Great Ormond Street Hospital
Susan L. Hamilton: Baylor College of Medicine

Nature Communications, 2017, vol. 8, issue 1, 1-15

Abstract: 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.

Date: 2017
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DOI: 10.1038/ncomms14659

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