A chemical chaperone improves muscle function in mice with a RyR1 mutation
| العنوان: | A chemical chaperone improves muscle function in mice with a RyR1 mutation |
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| المؤلفون: | Corey L. Reynolds, Amy D. Hanna, Hui J. Wang, Yan Xia, George G. Rodney, Cheng Long, William R. Lagor, Keke Dong, Hisayuki Amano, Ergun Sahin, John C. Martin, Dimitra K. Georgiou, Mark Knoblauch, Aditya D. Joshi, Adan Dagnino-Acosta, Chang Seok Lee, Susan L. Hamilton, Jianjun Xu, Caroline Sewry |
| المصدر: | Nature Communications, Vol 8, Iss 1, Pp 1-15 (2017) Nature Communications |
| بيانات النشر: | Nature Portfolio, 2017. |
| سنة النشر: | 2017 |
| مصطلحات موضوعية: | Male, 0301 basic medicine, Science, Muscle Proteins, General Physics and Astronomy, Apoptosis, Biology, Calsequestrin, Phenylbutyrate, Article, General Biochemistry, Genetics and Molecular Biology, 03 medical and health sciences, 0302 clinical medicine, medicine, Animals, Calcium Signaling, Muscle, Skeletal, Myopathy, RYR1, Multidisciplinary, Ryanodine receptor, Endoplasmic reticulum, Ryanodine Receptor Calcium Release Channel, General Chemistry, Endoplasmic Reticulum Stress, musculoskeletal system, Phenylbutyrates, Molecular biology, Mice, Mutant Strains, Mitochondria, 3. Good health, Cell biology, Mice, Inbred C57BL, Oxidative Stress, Phenotype, 030104 developmental biology, Triadin, Mutation, Unfolded protein response, Calcium, medicine.symptom, Carrier Proteins, Reactive Oxygen Species, tissues, 030217 neurology & neurosurgery, Signal Transduction |
| الوصف: | 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. Mutations in the RyR1 channel cause core myopathies. Here the authors show that ER stress and the unfolded protein response underlie the pathology caused by a common RyR1 channel mutation, and show that treatment with a chemical chaperone restores muscle function in mice. |
| اللغة: | English |
| تدمد: | 2041-1723 |
| الوصول الحر: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::66e84c20b95dcf268f683054bd66cc5dTest https://doaj.org/article/8a7faf752203416684267602ebe0758bTest |
| حقوق: | OPEN |
| رقم الانضمام: | edsair.doi.dedup.....66e84c20b95dcf268f683054bd66cc5d |
| قاعدة البيانات: | OpenAIRE |
| تدمد: | 20411723 |
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