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RESEARCH PRODUCT
Increased Muscleblind levels by chloroquine treatment improve myotonic dystrophy type 1 phenotypes in in vitro and in vivo models
Adolfo López De MunainJorge Espinosa-espinosaMaria Sabater-arcisMiren ZulaicaAriadna BargielaRuben Arterosubject
0301 basic medicinemusculoskeletal diseasesMaleRNA SplicingRNA-binding proteinBiologyMyotonic dystrophychloroquinemuscleblindMyoblasts03 medical and health scienceschemistry.chemical_compoundMice0302 clinical medicineIn vivomedicineAutophagyMBNL1AnimalsDrosophila ProteinsHumansMyotonic DystrophytherapyMultidisciplinarymyotonic dystrophyMusclesRNANuclear ProteinsRNA-Binding ProteinsChloroquinemedicine.diseaseMyotoniaCell biologyDNA-Binding ProteinsDisease Models Animal030104 developmental biologyPhenotypechemistryPNAS PlusRNA splicingDrosophilaFemaleTrinucleotide repeat expansion030217 neurology & neurosurgerydescription
Myotonic dystrophy type 1 (DM1) is a life-threatening and chronically debilitating neuromuscular disease caused by the expansion of a CTG trinucleotide repeat in the 3′ UTR of the DMPK gene. The mutant RNA forms insoluble structures capable of sequestering RNA binding proteins of the Muscleblind-like (MBNL) family, which ultimately leads to phenotypes. In this work, we demonstrate that treatment with the antiautophagic drug chloroquine was sufficient to up-regulate MBNL1 and 2 proteins in Drosophila and mouse (HSA LR ) models and patient-derived myoblasts. Extra Muscleblind was functional at the molecular level and improved splicing events regulated by MBNLs in all disease models. In vivo, chloroquine restored locomotion, rescued average cross-sectional muscle area, and extended median survival in DM1 flies. In HSA LR mice, the drug restored muscular strength and histopathology signs and reduced the grade of myotonia. Taken together, these results offer a means to replenish critically low MBNL levels in DM1.
| year | journal | country | edition | language |
|---|---|---|---|---|
| 2019-11-21 |