Increased Muscleblind levels by chloroquine treatment improve myotonic dystrophy type 1 phenotypes in in vitro and in vivo models
Por:
A. BARGIELA, M. SABATER-ARCIS, J. ESPINOSA-ESPINOSA, M. ZULAICA, A. DE MUNAIN and R. ARTERO
Publicada:
10 dic 2019
Resumen:
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 (HSALR) 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 HSALR 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.
Filiaciones:
:
Incliva Hlth Res Inst, Translat Genom Grp, Valencia 46010, Spain
Univ Valencia, Interdisciplinary Res Struct Biotechnol & Biomed, E-46100 Valencia, Spain
Incliva Hlth Res Inst, Principe Felipe Res Ctr, Valencia 46010, Spain
:
Incliva Hlth Res Inst, Translat Genom Grp, Valencia 46010, Spain
Univ Valencia, Interdisciplinary Res Struct Biotechnol & Biomed, E-46100 Valencia, Spain
Incliva Hlth Res Inst, Principe Felipe Res Ctr, Valencia 46010, Spain
:
Incliva Hlth Res Inst, Translat Genom Grp, Valencia 46010, Spain
Univ Valencia, Interdisciplinary Res Struct Biotechnol & Biomed, E-46100 Valencia, Spain
Incliva Hlth Res Inst, Principe Felipe Res Ctr, Valencia 46010, Spain
M. ZULAICA:
Inst Biodonostia, Neurosci Area, San Sebastian 20014, Spain
Minist Sci Innovat & Univ, Ctr Biomed Res Neurodegenerat Dis CIBERNED, Madrid 28031, Spain
A. DE MUNAIN:
Inst Biodonostia, Neurosci Area, San Sebastian 20014, Spain
Minist Sci Innovat & Univ, Ctr Biomed Res Neurodegenerat Dis CIBERNED, Madrid 28031, Spain
Hosp Univ Donostia, Dept Neurol, San Sebastian 20014, Spain
Univ Basque Country, Sch Med & Nursery, Dept Neurosci, San Sebastian 20014, Spain
:
Incliva Hlth Res Inst, Translat Genom Grp, Valencia 46010, Spain
Univ Valencia, Interdisciplinary Res Struct Biotechnol & Biomed, E-46100 Valencia, Spain
Incliva Hlth Res Inst, Principe Felipe Res Ctr, Valencia 46010, Spain
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