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

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

PROVIDER: PRJNA529068 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR8786370_1.fastq.gz	Fastqsanger.gz
	SRR8786370_2.fastq.gz	Fastqsanger.gz
	SRR8786371_1.fastq.gz	Fastqsanger.gz
	SRR8786371_2.fastq.gz	Fastqsanger.gz
	SRR8786372_1.fastq.gz	Fastqsanger.gz

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

Project description: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.

2019-11-22 | GSE128844 | GEO

Muscleblind-like compound knockout models for myotonic dystrophy

Project description:Myotonic dystrophy (DM) is a multi-systemic disease that severely impacts cardiac and skeletal muscle functions as well as the central nervous system. DM is unusual because it is RNA-mediated disease due to the expression of C(C)UG expansion RNAs that inhibit the activities of the muscleblind-like (MBNL) proteins. In mice, studies using Mbnl1 and Mbnl2 single knockouts have revealed that Mbnl1 plays a predominant role in skeletal and heart muscle alternative splicing regulation while Mbnl2 performs an analogous splicing function in the brain. However, Mbnl single knockout models fail to recapitulate the full-range of adult-onset DM muscle symptoms. Here, we report that Mbnl1; Mbnl2 double knockouts are embryonic lethal while Mbnl1-/-; Mbnl2+/- mice, which express no Mbnl1 and reduced levels of Mbnl2, are viable but develop cardinal features of adult-onset DM cardiac and skeletal muscle disease including reduced lifespan, heart conduction block, severe myotonia and progressive skeletal muscle weakness. Mbnl2 protein levels are elevated in both Mbnl1-/- and Mbnl1-/-; Mbnl2+/- knockouts where Mbnl2 targets Mbnl1-regulated exons. These findings support the MBNL loss-of-function model for DM and provide novel Mbnl compound knockout models to investigate the molecular pathways disrupted by RNA-mediated disease. Mbnl2 protein-RNA interactions were assessed in 4-month-old WT and Mbnl1-/- quadriceps muscles in triplicates by HITS-CLIP.

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Compound loss of muscleblind-like function in myotonic dystrophy

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Effect of myotonic dystrophy on pre-mRNA alternative splicing in skeletal muscle

Project description:Misregulated alternative splicing appears to be a major factor in the pathogenesis of myotonic dystrophy. The present study was done to further explore alternative splicing in this condition by doing exon-level analysis of mRNA from skeletal muscle of 8 subjects with type 1 myotonic dystrophy, 7 subjects with type 2 myotonic dystrophy, 8 disease controls (subjects with facioscapulohumeral muscular dystrophy), and 8 healthy controls . The ratios of signals from the various exons of a gene provided an index of altered exon inclusion/exclusion that was independent of the overall expression of that gene. There were numerous transcripts for which there was evidence of abnormal alternative splicing in subjects with myotonic dystrophy. For many of these transcripts, the abnormal splicing was confirmed by an independent RT-PCR approach. 31 subjects, one sample per subject, four groups: healthy subjects (n = 8), facioscapulohumeral dystrophy (n = 8), type 1 myotonic dystrophy (n = 8), type 2 myotonic dystrophy (n = 7)

2013-06-15 | E-GEOD-47968 | biostudies-arrayexpress

Transcriptional profiling of Myotonic dystrophy muscle and heart

Project description:Autopsy and biopsy muscle and heart tissue was collected from consented human subjects with and without confirmed myotonic dystrophy type 1, myotonic dystrophy type 2, or Duchenne muscular dystrophy. RNA was isolated for preparation of RNAseq libraries and sequenced on the Illumina platform.

2016-09-29 | GSE86356 | GEO

Reversal of RNA toxicity in myotonic dystrophy via a decoy RNA-binding protein with high affinity for expanded CUG repeats [mouse]

Project description:Myotonic dystrophy type 1 (DM1) is an RNA-dominant disease whose pathogenesis stems from the functional loss of muscleblind-like RNA-binding proteins (RBPs), which causes the formation of alternative-splicing defects. The loss of functional muscleblind-like protein 1 (MBNL1) results from its nuclear sequestration by mutant transcripts containing pathogenic expanded CUG repeats (CUGexp). Here we show that an MBNL1∆ RBP engineered to act as a decoy for CUGexp reverses the toxicity of the mutant transcripts.

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Reversal of RNA toxicity in myotonic dystrophy via a decoy RNA-binding protein with high affinity for expanded CUG repeats [human]

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Effect of myotonic dystrophy on pre-mRNA alternative splicing in skeletal muscle

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Transcriptional profiling by array of human cataract samples to study the involvement of Type 1 interferon signalling in myotonic dystrophy types I and II

Project description:Comparison of myotonic dystrophy cataract samples with control non-myotonic dystrophy cataract samples

2011-10-31 | E-MEXP-3365 | biostudies-arrayexpress

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

Project description: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.

| S-EPMC6911202 | biostudies-literature

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