Splicing changes in gastrocnemius muscle from 3-month-old HSALR mice
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ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE226676 | GEO | 2024/06/06
REPOSITORIES: GEO
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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
Project description:Distinct RNA-mediated impacts on alternative splicing and extracellular matrix gene expression in a mouse model of myotonic dystrophy. Myotonic dystrophy (DM1) is associated with expression of expanded CTG DNA repeats as RNA (CUGexp RNA). To test whether CUGexp RNA creates a global splicing defect, we compared skeletal muscle of two mouse DM1 models, one expressing a CTGexp transgene, and another homozygous for a defective Mbnl1 gene. Strong correlation in splicing changes for ~100 new Mbnl1-regulated exons indicates loss of Mbnl1 explains >80% of the splicing pathology due to CUGexp RNA. In contrast, only about half of mRNA level changes can be attributed to loss of Mbnl1, indicating CUGexp RNA has Mbnl1-independent effects, particularly on mRNAs for extracellular matrix (ECM) proteins. We propose that CUGexp RNA causes two separate effects: loss of Mbnl1 function, disrupting splicing, and loss of another function that disrupts ECM mRNA regulation, possibly mediated by MBNL2. These findings reveal unanticipated similarities between DM1 and other muscular dystrophies. MBNL1 knockout and HSALR mice on FVB background. To test whether CUGexp RNA creates a global splicing defect, we compared skeletal muscle of two mouse DM1 models, one expressing a CTGexp transgene, and another homozygous for a defective Mbnl1 gene. These samples were compared to the skeletal muscle of a wildtype mouse.
2010-01-23 | E-GEOD-17986 | biostudies-arrayexpress
Project description:Myotonic dystrophy type 1 (DM1) is an RNA dominant disease in which mutant transcripts containing an expanded CUG repeat (CUGexp) cause muscle dysfunction by interfering with biogenesis of other mRNAs. The toxic effects of mutant RNA are mediated partly through sequestration of splicing regulator Muscleblind-like 1 (Mbnl1), a protein that binds to CUGexp RNA. A gene that is prominently affected encodes chloride channel 1 (Clcn1), resulting in hyperexcitability of muscle (myotonia). To identify DM1-affected genes and study mechanisms for dysregulation, we performed global mRNA profiling in transgenic mice that express CUGexp RNA, as compared to Mbnl1 knockout and Clcn1 null mice. We found that the majority of changes induced by CUGexp RNA in skeletal muscle can be explained by reduced activity of Mbnl1, including many changes that are secondary to myotonia. The pathway most affected comprises genes involved in calcium signaling and homeostasis. Some effects of CUGexp RNA on gene expression are caused by abnormal alternative splicing or downregulation of Mbnl1-interacting mRNAs. However, several of the most highly dysregulated genes showed altered transcription, as indicated by parallel changes of the corresponding premRNAs. These results support the idea that trans-dominant effects of CUGexp RNA on gene expression in this transgenic model may occur at the level of transcription, RNA processing, and mRNA decay, and are mediated mainly but not entirely through sequestration of Mbnl1. Experiment Overall Design: All experiments involved generating expression profiles of quadriceps muscles taken from mice. Experiments 1 and 2: samples were hybridized to Moe430A and Moe430B arrays. Experiment 3: samples were hybridized to Mouse Genome 430 2.0 array. Experiment 1 compared expression profiles of wild-type mice (FVB strain) with two lines, designated 20b and 41, of CUGexp transgenic mice with FVB background. Experiment 2 compared expression profiles of Clcn1-null (myotonic) mice with the wild-type background strain (BALB). Experiment 3 compared expression profiles of Mbnl1-null mice with the wild-type background strain (FVB).
2009-02-13 | E-GEOD-14691 | biostudies-arrayexpress
Project description:In the context of developing an integrative proteogenomics strategy for assessing both differential gene expression and alternative splicing, we generated RNA-seq data (paired-end, 76 bp, 71 million reads per sample on average) from gastrocnemius muscles (right and left hind limb) from five wild-type mice and five HSALR mice (male, 10-12 weeks old) modelling the human disease Myotonic Dystrophy type 1 (DM1).
2023-06-30 | E-MTAB-10842 | biostudies-arrayexpress
Project description:In order to examine the changes in gene expression between normal and myotonic dystrophic animals, gene expression array studies were done with extensor digitorum longus (EDL) of transgenic HSALR line 20b mice using Affymetrix MOE430 2.0 microarrays. We used EDL muscle from transgenic HSALR line 20b mice, maintained as homozygotes in an FVB inbred background and wild-type FVB mice purchased from Taconic.
2012-10-21 | GSE24920 | GEO
Project description:Here, we performed a large-scale coordinated transcriptomic and proteomic analysis to characterize a DM1 mouse model (HSALR) in comparison to wild-type. Our integrative proteogenomics approach comprised gene- and splicing-level assessments for mRNA and protein. It recapitulated many known instances of aberrant mRNA splicing in DM1 and identified new ones. It enabled the design and targeting of splicing-specific peptides and confirmed the translation of known instances of aberrantly spliced disease-related genes (e.g. Atp2a1, Bin1, Ryr1), complemented by novel findings (e.g. Ywhae, Flnc, Svil). Comparative analysis of large-scale mRNA and protein expression data showed remarkable agreement of differential patterns between disease and wild-type on both the gene and especially the splicing level.
2024-01-26 | PXD025589 | Pride
Project description:In order to examine the changes in gene expression between normal and myotonic dystrophic animals, gene expression array studies were done with extensor digitorum longus (EDL) of transgenic HSALR line 20b mice using Affymetrix MOE430 2.0 microarrays. We used EDL muscle from transgenic HSALR line 20b mice, maintained as homozygotes in an FVB inbred background and wild-type FVB mice purchased from Taconic. Affymetrix gene expression arrays were performed on HSALR and wild type EDL muscle
2012-10-21 | E-GEOD-24920 | biostudies-arrayexpress
Project description:Antisense oligonucleotides (ASOs) strategies for DM1 can abolish the toxic RNA gain-of-function mechanism caused by nuclear-retained mutant DMPK transcripts containing CUG expansions (CUGexp). However, systemic use of ASOs for this muscular disease remains challenging due to poor drug distribution to skeletal muscle. To overcome this limitation, we test an arginine-rich Pip6a cell-penetrating peptide and show that Pip6a-conjugated PMO dramatically enhanced ASO delivery into striated muscles of DM1 mice following systemic administration in comparison to unconjugated PMO and other ASO strategies. Thus, low dose treatment of Pip6a-PMO-CAG targeting pathologic expansions is sufficient to reverse both splicing defects and myotonia in DM1 mice and normalizes the overall disease-transcriptome.
2019-07-27 | GSE134926 | GEO
Project description:Introduction: Myotonic dystrophy of type 1 (DM1), the most common dystrophy in adults, is an autosomal dominant inherited disease, affecting around 1 in 8000 person. Patients suffering from DM1 develop essentially muscle disorders such as myotonia, muscle weakness, muscle loss and atrophy. The disease is caused by the mutation of the DMPK "Dystrophia Myotonica Protein Kinase" gene. The mutation correspond to an abnormally large expansion of CTG tri-nucleotides repeats located in the 3'-untranslated region of this gene. Expanded CTG repeats are normally transcribed, but accumulates in RNA aggregates that sequester RNA-binding proteins such as the splicing regulator MBNL1. Consequently, due to MBNL1 sequestration, DM1 is characterized by aberrant splicing of a wide number of mRNA, which are themselves responsible for the symptoms observed in the disease. Purpose: To determine as much as possible novel splicing misregulations taking place in DM1 skeletal muscle, we performed a paired-end RNA sequencing (RNA-seq) using muscles samples of normal individuals (CTRL, n=3) versus muscles of DM1 patients (DM1, n=3). The data was analyzed by a bioinformatical software, called MISO, in order to map the alternative splicing changes between normal and DM1 muscle. The aim of this study was to get a broad and precise view of the splicing changes occurring in DM1 muscle.
2017-08-24 | GSE85984 | GEO
Project description:Myotonic Dystrophy (DM1) is a rare neuromuscular disease caused by the expansion of unstable CTG repeats in a non-coding region of the DMPK gene. CUG expansions in mutant DMPK transcripts fold into hairpins that sequester MBNL1 proteins in ribonuclear foci, depletion of MBNL1 being a chief contribution to disease symptoms such as muscle weakness and atrophy, and myotonia. Thus, the upregulation of endogenous MBNL1 levels may compensate for the sequestration. We have demonstrated that antisense oligonucleotides against miR-218 boost expression of MBNL1 and rescue phenotypes in disease models. Here we provide a preclinical characterization of an antagomiR-218 molecule using the HSALR mouse model and patient-derived myoblasts. In HSALR, antagomiR-218 rescued molecular and functional phenotypes in a dose-dependent manner, showed a good toxicity profile, and lasted some 15 days after a single subcutaneous injection. In muscle tissue, the antagomiR rescued the normal subcellular distribution of Mbnl1 and did not alter the percentage of myonuclei containing CUG foci. In patient-derived cells, antagomiR-218 improved defective fusion and differentiation and rescued up to 34% of the gene expression alterations found in the transcriptome of patient myoblasts. Importantly, miR-218 was found upregulated in DM1 muscle biopsies, which makes this miRNA a relevant therapeutic target.
2021-01-31 | GSE158216 | GEO