Increased Muscleblind levels by chloroquine treatment improves myotonic dystrophy type 1 phenotypes in in vitro and in vivo models

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 originates phenotypes. In this work we demonstrate that treatment with the anti-autophagic drug chloroquine in Drosophila and mouse (HSALR) models, and patient-derived myoblasts, was sufficient to upregulate MBNL1 and 2 proteins. Extra Muscleblind was functional at the molecular level and improved splicing events regulated by MBNLs in all disease models. In vivo, chloroquine rescued locomotion and average crossectional muscle area, and extended median survival of DM1 flies. In HSALR mice the drug recovered muscular strength and histopathology signs, and reduced myotonia grade. Taken together these results offer a novel means to replenish the critically low levels of MBNLs in DM1. Overall design: We have 3 replicas of each treatment: Control, Disease, TreatmentConcentration1, TreatmentConcentration2