Back to Search
Start Over
A chemical chaperone improves muscle function in mice with a RyR1 mutation
- Source :
- Nature Communications, Vol 8, Iss 1, Pp 1-15 (2017), Nature Communications
- Publication Year :
- 2017
- Publisher :
- Nature Portfolio, 2017.
-
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.<br />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.
- Subjects :
- 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
Subjects
Details
- Language :
- English
- ISSN :
- 20411723
- Volume :
- 8
- Issue :
- 1
- Database :
- OpenAIRE
- Journal :
- Nature Communications
- Accession number :
- edsair.doi.dedup.....66e84c20b95dcf268f683054bd66cc5d