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

被引：57

作者：

Lee, Chang Seok ^{[1
]}

Hanna, Amy D. ^{[1
]}

Wang, Hui ^{[1
]}

Dagnino-Acosta, Adan ^{[1
]}

Joshi, Aditya D. ^{[1
]}

Knoblauch, Mark ^{[1
]}

Xia, Yan ^{[1
]}

Georgiou, Dimitra K. ^{[1
]}

Xu, Jianjun ^{[1
]}

Long, Cheng ^{[1
]}

Amano, Hisayuki ^{[1
]}

Reynolds, Corey ^{[1
]}

Dong, Keke ^{[1
]}

Martin, John C. ^{[1
]}

Lagor, William R. ^{[1
]}

Rodney, George G. ^{[1
]}

Sahin, Ergun ^{[1
]}

Sewry, Caroline ^{[2
,3
]}

Hamilton, Susan L. ^{[1
]}

机构：

[1] Baylor Coll Med, Dept Mol Physiol & Biophys, One Baylor Plaza, Houston, TX 77030 USA

[2] UCL Inst Child Hlth, Dubowitz Neuromuscular Ctr, 30 Guilford St, London WC1N 1EH, England

[3] Great Ormond St Hosp Sick Children, 30 Guilford St, London WC1N 1EH, England

来源：

NATURE COMMUNICATIONS | 2017年 / 8卷

基金：

美国国家卫生研究院;

关键词：

CENTRAL CORE DISEASE; RELEASE CHANNEL FUNCTION; SKELETAL-MUSCLE; RYANODINE RECEPTOR; ENDOPLASMIC-RETICULUM; SARCOPLASMIC-RETICULUM; CONGENITAL MYOPATHIES; MITOCHONDRIAL CA2+; CLINICAL-FEATURES; PROTEIN-SYNTHESIS;

D O I：

10.1038/ncomms14659

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

07 ; 0710 ; 09 ;

摘要：

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.

引用

页数：15

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