A chemical chaperone improves muscle function in mice with a RyR1 mutation.
Chang Seok LeeAmy D HannaHui J WangAdan Dagnino-AcostaAditya D JoshiMark KnoblauchYan XiaDimitra K GeorgiouJianjun XuCheng LongHisayuki AmanoCorey ReynoldsKeke DongJohn C MartinWilliam R LagorGeorge G RodneyErgun SahinCaroline SewrySusan L HamiltonPublished in: Nature communications (2017)
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.
Keyphrases
- endoplasmic reticulum
- wild type
- skeletal muscle
- high fat diet induced
- protein kinase
- randomized controlled trial
- oxidative stress
- heart rate
- type diabetes
- early onset
- heat shock protein
- gene expression
- emergency department
- late onset
- dna methylation
- heat shock
- blood pressure
- binding protein
- endoplasmic reticulum stress
- drug induced
- heart rate variability
- reactive oxygen species
- genome wide
- risk assessment
- metabolic syndrome
- brain injury
- blood brain barrier
- replacement therapy
- muscular dystrophy
- functional connectivity
- duchenne muscular dystrophy
- adverse drug