Browse
Submit Data
Databases
API
Help

Dataset Information

0 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

The effect of utrophin on the electrophysiological properties of DMD hiPSC-derived cardiomyocytes

ABSTRACT: DMD is a genetic disease, which leads to muscle weakness and cardiomyopathy. The latter remains incurable, being the main cause of death in DMD, therefore new therapeutic strategies are being sought to provide effective treatment. One of them considers upregulation of utrophin, a protein structurally and functionally homologous to dystrophin. In this study proteomic analysis of dystrophin-deficient and both dystrophin- and utrophin-deficient hiPSC-CM indicated on considerable differences in terms of contraction-related mechanisms. We thus investigated the role of utrophin in the maintenance of electrophysiological properties of DMD hiPSC-CM using the cells with additional utrophin deficiency and with utrophin upregulation. Obtained results indicated on disturbance of calcium handling in DMD hiPSC-CM, even more pronounced in DMD/UTRN KO hiPSC-CM and increased values of AHP in DMD hiPSC-CM. Utrophin upregulation improved both calcium oscillations and AHP values. Our findings highlight utrophin as important in the maintenance of the electrophysiological properties of DMD hiPSC-CM.

INSTRUMENT(S): Orbitrap Eclipse

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Heart

SUBMITTER: Luisa Marie Schmidt

LAB HEAD: Józef Dulak

PROVIDER: PXD044407 | Pride | 2024-06-20

REPOSITORIES: Pride

ACCESS DATA

Json Xml

Similar Datasets

IPSC derived cardiac fibroblasts of DMD patients show compromised actin microfilaments, metabolic shift and pro-fibrotic phenotype.

Project description:Duchenne muscular dystrophy (DMD) is a severe form of muscular dystrophy caused by mutations in the dystrophin gene. We characterized which isoforms of dystrophin were expressed by human induced pluripotent stem cell (hiPSC)-derived cardiac fibroblasts obtained from control and DMD patients. Distinct dystrophin isoforms were observed; however, the highest molecular weight isoform was absent in DMD patients carrying exon deletions or mutations in the dystrophin gene. The loss of the full-length dystrophin isoform in hiPSC-derived cardiac fibroblasts from DMD patients resulted in deficient formation of actin microfilaments and a metabolic switch from mitochondrial oxidation to glycolysis. The DMD hiPSC-derived cardiac fibroblasts exhibited a dysregulated mitochondria network and reduced mitochondrial respiration, with enhanced compensatory glycolysis to sustain cellular ATP production. This metabolic remodeling was associated with an exacerbated myofibroblast phenotype and increased fibroblast activation in response to pro fibrotic challenges. As cardiac fibrosis is a critical pathological feature of the DMD heart, the myofibroblast phenotype induced by the absence of dystophin may contribute to deterioration in cardiac function. Our study highlights therelationship between cytoskeletal dynamics, metabolism of the cell and myofibroblast differentiation and provides a new mechanism by which inactivation of dystrophin in non-cardiomyocyte cells may increase the severity of cardiopathy.

2023-09-30 | GSE237014 | GEO

Systemic deletion of DMD exon 51 rescues clinically severe Duchenne muscular dystrophy in a pig model lacking DMD exon 52

Project description:Duchenne muscular dystrophy (DMD) is a fatal X-linked disease caused by mutations in the dystrophin (DMD) gene, leading to the complete absence of DMD and progressive degeneration of skeletal and heart muscles. Expression of an internally shortened dystrophin in DMD subjects (DMDΔ52) can be achieved by skipping DMD exon 51 to reframe the transcript. To predict the best possible outcome of this therapeutic strategy, we generated transgenic pigs lacking DMD exon 51 and 52, additionally representing a new model for Becker muscular dystrophy (BMD). To inspect the proteome alterations caused by the different dystrophin mutations in an unbiased and comprehensive manner, we performed a label-free liquid chromatography-tandem mass spectrometry analysis (LC-MS/MS) of myocardial and skeletal muscle samples from wild-type (WT), DMDΔ52 and DMDΔ51-52 pigs.

2023-07-11 | PXD039533 | Pride

Deletion of DMD exon 52 in the pig results in fulminant muscular dystrophy

Project description:Duchenne muscular dystrophy (DMD) is caused by mutations in the X-linked dystrophin (DMD) gene. The absence of dystrophin protein leads to progressive muscle weakness and wasting, disability and death. To establish a tailored large animal model of DMD, we deleted DMD exon 52 in male pig cells by gene targeting and generated offspring by nuclear transfer. DMD pigs exhibit absence of dystrophin in skeletal muscles, increased serum creatine kinase levels, progressive dystrophic changes of skeletal muscles, impaired mobility, muscle weakness, and a maximum life span of 3 months due to respiratory impairment. To address the accelerated development of muscular dystrophy in DMD pigs as compared to human patients, we performed a genome-wide transcriptome study of M. biceps femoris samples from 2-day-old and 3-month-old DMD and age-matched wild-type pigs. The transcriptome changes in 3-month-old DMD pigs were in good accordance with the findings of gene expression profiles in human DMD, reflecting the processes of degeneration, regeneration, inflammation, fibrosis, and impaired metabolic activity. The transcriptome profile of 2-day-old DMD pigs pointed towards increased protein and DNA catabolism, reduced extracellular matrix formation and cell proliferation and showed similarities with transcriptome changes induced by exercise injury in muscle. Our transcriptome studies provide new insights into congenital changes associated with dystrophin deficiency and secondary complications arising during postnatal development. Thus the DMD pig is a useful model to determine the hierarchy of physiological derangements in dystrophin-deficient muscle. 13 samples, two conditions, two age-groups, 3-4 biological replicates

2013-08-06 | E-GEOD-44096 | biostudies-arrayexpress

Loss of full-length dystrophin expression causes major cell-autonomous abnormalities in proliferating myoblasts

Project description:Duchenne muscular dystrophy (DMD) is a severely debilitating and incurable neuromuscular disease. Its conspicuous feature is the absence of dystrophin in myofibers and therefore most therapeutic approaches focus on some form of its re-expression there. However, increasing body of evidence points at an early developmental onset of DMD and severe abnormalities were uncovered in dystrophic muscle stem cells. In this study, we explore gene expression changes in primary myoblasts from mice lacking expression of the full length dystrophin transcript. Total RNA extracted from primary myoblasts isolated from gastrocnemii of 8 week old male Dmd-mdx (MDX - lacking the full length dystrophin transcript), Dmd-mdx-βgeo (BGEO - lacking all dystrophin expression) and control mice (WT) were subjected to RNA sequencing following ribodepletion, and analysed for the differential expression of genes between groups and the enrichment of gene ontology categories or pathways.

2022-09-14 | E-MTAB-10322 | biostudies-arrayexpress

Deletion of DMD exon 52 in the pig results in fulminant muscular dystrophy

2013-08-06 | GSE44096 | GEO

The DMD locus harbours multiple long non-coding RNAs which orchestrate and control transcription of muscle dystrophin mRNA isoforms

Project description:The 2.2 Mb long dystrophin (DMD) gene, the largest gene in the human genome, corresponds to roughly 0.1% of the entire human DNA sequence. Mutations in this gene cause Duchenne muscular dystrophy and other milder X-linked, recessive dystrophinopathies. Using a custom-made tiling array, specifically designed for the DMD locus, we identified a variety of novel long non-coding RNAs (ncRNAs), both sense and antisense oriented, whose expression profiles mirror that of DMD gene. Importantly, these transcripts are intronic in origin and specifically localized to the nucleus and are transcribed contextually with dystrophin isoforms or primed by MyoD-induced myogenic differentiation. Furthermore, their forced ectopic expression in both human muscle and neuronal cells causes a specific and negative regulation of endogenous dystrophin full length isoforms and significantly down-regulate the activity of a luciferase reporter construct carrying the minimal promoter regions of the muscle dystrophin isoform. Consistent with this apparently repressive role, we found that, in muscle samples of DMD symptomatic female carriers, lncRNAs expression levels inversely correlate with those of muscle full length DMD isoforms. Overall these findings unveil an unprecedented complexity of the transcriptional pattern of the DMD locus and reveal that DMD-specific lncRNAs may contribute to the orchestration and homeostasis of the muscle dystrophin expression pattern by selective targeting and down-modulation of dystrophin promoter transcriptional activity.

2011-06-05 | GSE27068 | GEO

Gene expression and chromatin organization changes in lamin A/C haploinsufficient human induced pluripotent stem cell-derived cardiomyocytes [Hi-C]

Project description:Pathogenic mutations in A-type nuclear lamins may dysregulate gene expression due to changes in chromatin organization into active (A) and inactive (B) compartments. To test this, we performed genome-wide chromosome conformation analyses (Hi-C) and transcriptome profiling (RNA-seq) in human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CM) with a haploinsufficient mutation for Lamin A/C that causes cardiac laminopathy. Mutant hiPSC-CM have marked electrophysiological, contractile, and gene expression alterations. While large-scale changes in chromatin topology are evident, differences in chromatin compartmentalization are limited to a few hotspots. These regions normally transition from A to B during cardiogenesis, but remain in A in mutant hiPSC-CM. Non-cardiac genes located within such aberrant domains are ectopically expressed, including the neuronal P/Q-type calcium channel CACNA1A. Pharmacological inhibition of the resulting currents partially mitigates elongation of field potential duration in mutant hiPSC-CM. On the other hand, A/B compartment changes do not explain most gene expression alterations observed in mutant hiPSC-CM, putting in perspective the role of chromatin organization dysregulation in cardiac laminopathy.

2019-02-13 | GSE126459 | GEO

Gene expression and chromatin organization changes in lamin A/C haploinsufficient human induced pluripotent stem cell-derived cardiomyocytes [RNA-seq]

2019-02-13 | GSE126458 | GEO

In vivo genome editing restores dystrophin expression in Duchenne muscular dystrophy patient muscle fibers [Nanopore sequencing]

Project description:Duchenne muscular dystrophy (DMD) is the most common fatal genetic disease. Clustered regularly interspaced short palindromic repeat (CRISPR)-mediated gene editing is a promising strategy for permanently curing DMD. In this study we developed a novel strategy for reframing DMD mutations by CRISPR-mediated large-scale excision of exons 46–54. We compared this approach to other DMD rescue strategies using DMD patient-derived primary muscle-derived stem cells (MDSCs) and found that it showed the highest efficiency in terms of restoring of dystrophin protein expression. We also confirmed that CRISPR from Prevotella and Francisella 1(Cpf1)-mediated genome editing could correct DMD mutation with higher specificity than CRISPR-associated protein 9 (Cas9). Furthermore, A patient-derived xenograft (PDX) DMD mouse model was established by transplanting DMD-MDSCs into immunodeficient mice. CRISPR gene editing components were intramuscularly delivered into the mouse model by adeno-associated virus vectors. Dystrophin expression levels were increased by 10%–30% in human DMD muscle fibers. The restored dystrophin in vivo was functional, as demonstrated by the expression of the dystrophin glycoprotein complex member β-dystroglycan. This study provides a sensitive indicator for in vivo efficacy of gene editing and lays the foundation for a clinical trial of DMD treatment with gene editing technology.

2021-02-28 | GSE167584 | GEO

In vivo genome editing restores dystrophin expression in Duchenne muscular dystrophy patient muscle fibers [GUIDE-seq]

2021-02-28 | GSE167583 | GEO

OmicsDI is part of the ELIXIR infrastructure

OmicsDI is an Elixir interoperability service. Learn more ›

OmicsDI Databases

PRIDE
PeptideAtlas
MassIVE
JPOST Repository
Physiome Model Repository

EGA
EVA
ENA
LINCS
PAXDB
Cell Collective

MetaboLights
Metabolomics Workbench
MetabolomeExpress
GNPS
BioModels
FAIRDOMHub

ArrayExpress
dbGaP
ExpressionAtlas
GEO
NODE

Information

Databases
Help
API
Contact us
Code on GitHub
Terms of use
Submit Data