MiR-486 is an epigenetic modulator of Duchenne muscular dystrophy pathologies [RNA-seq]
Ontology highlight
ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE178772 | GEO | 2022/10/01
REPOSITORIES: GEO
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Project description:Duchenne muscular dystrophy (DMD) is an X-linked progressive muscle disorder resulting in muscle weakness and cardiomyopathy. MicroRNAs have shown to play a significant role in muscle development, metabolism, and disease pathologies. We demonstrated that miR-486 expression is reduced in DMD muscles and its expression levels correlate with dystrophic disease severity. miR-486 knockout mice developed disrupted myofiber architecture, decreased myofiber size, decreased locomotor activity, increased fibrosis, and metabolic defects that were exacerbated on the dystrophic mdx5cv background. We integrated RNA-sequencing and chimeric eCLIP-sequencing data to identify direct in vivo targets of miR-486 and associated dysregulated gene signatures in skeletal muscle. Together, our studies identify miR-486 as a driver of muscle remodeling in DMD, a useful biomarker for dystrophic disease progression, and highlight chimeric eCLIP-sequencing as a useful tool to identify direct in vivo microRNA target transcripts.
2022-05-04 | GSE173821 | GEO
Project description:Infiltrating macrophages contribute to muscle dystrophic changes in Duchenne muscular dystrophy (DMD). In a DMD mouse model, mdx5cv mice, CC chemokine receptor type 2 (CCR2) deficiency diminishes Ly6Chi macrophage infiltration by blocking blood Ly6Chi inflammatory monocyte recruitment. This is accompanied by transient improvement of muscle damage, fibrosis, and regeneration. The benefit is lost, however, after expansion of intramuscular Ly6Clo macrophages. To address mechanisms underlying the Ly6Clo macrophages expansion, we compared mdx5cv/Nur77-/- and mdx5cv/Ccr2-/-/Nur7-/- mice with mdx5cv and mdx5cv/Ccr2-/- mice, respectively, and found no evidence to suggest Ly6Clo monocyte recruitment by dystrophic muscles. Single-cell RNA sequencing analysis and Flt3cre/Rosa26LSL-YFP-based lineage tracing of macrophage origins demonstrated expansion and pathogenic activation of muscle resident macrophages in CCR2-deficient mdx5cv mice. The expansion was associated with increased cell proliferation, which appeared induced by colony stimulating factor 1 derived from fibro/adipogenic progenitors. Our study establishes a pathogenic role for skeletal muscle resident macrophages in muscular dystrophy.
2025-02-24 | GSE265803 | GEO
Project description:Cancer is considered as a disease of a specific organ, but its effects are felt throughout the body. The systemic effects of cancer can lead to weakness in muscles and heart, which hastens cancer-associated death. miR-486 is a myogenic microRNA and its reduced expression in skeletal muscle is observed in muscular dystrophy. Muscle-specific transgenic expression of miR-486 using muscle creatine kinase promoter (MCK-miR-486) partially rescues skeletal muscle defects in muscular dystrophy animal models. We had previously demonstrated reduced circulating and skeletal muscle levels of miR-486 in several cancer types and lower miR-486 levels correlated with skeletal muscle defects and functional limitations in mammary tumor models. Therefore, skeletal muscle defects induced by cancer could resemble defects observed in various dystrophies, which could be reversed through skeletal muscle expression of miR-486. We performed functional limitations studies and biochemical analysis of skeletal muscles of MMTV-Neu transgenic mice that mimic HER2+ breast cancer and MMTV-PyMT transgenic mice that mimic luminal subtype B breast cancer and these mice crossed to MCK-miR-486 transgenic mice. miR-486 significantly prevented tumor-induced reduction in muscle contraction force, grip strength, and rotarod performance in MMTV-Neu, but not in MMTV-PyMT mice. In MMTV-Neu model, miR-486 reversed several of the cancer-induced changes in skeletal muscle including loss of p53, phospho-AKT, and phospho-laminin alpha 2 (LAMA2) and gain of phosphorylation of the pre-mRNA processing factor hnRNPA0 and the splicing factor SRSF10. LAMA2 is a part of the dystrophin-associated glycoprotein complex, and its loss-of-function mutation is associated with congenital muscular dystrophy. Thus, similar to muscular dystrophy, miR-486 has the potential to reverse skeletal muscle defects and cancer burden in select cancer types.
2022-05-19 | PXD028554 | Pride
Project description:DOCK3 is a member of the DOCK family of guanine nucleotide exchange factors that function to regulate cell migration, fusion, and overall viability. Previously, we identified a miR-486/Dock3 signaling cascade that was dysregulated in dystrophin-deficient muscle which resulted in the overexpression of DOCK3, however not much else is known about the role of DOCK3 in muscle. In this work, we characterize the functional role of DOCK3 in normal and dystrophic striated muscle. By utilizing the Dock3 global knockout (Dock3 KO) mice, we found reducing Dock3 gene via haploinsufficiency in DMD mice improved muscle histology, however full loss of Dock3 worsened overall muscle function on a dystrophin-deficient background. Consistent with this, Dock3 KO mice have impaired muscle architecture, myoblast fusion defects, and cardiac functional deficits. Moreover, transcriptomic analyses of Dock3 knockout muscles reveal a decrease in factors known for myoblast fusion, suggesting a possible mechanism of action. These studies identify DOCK3 as a novel modulator of muscle fusion and muscle health, and may yield additional therapeutic targets for treating dystrophic muscle symptoms.
2020-12-24 | GSE141621 | GEO
Project description:We report here on the identification and functional characterization of Sca1-positive muscle interstitial cells that contribute to regeneration or fibroadipogenic degeneration of dystrophic muscles and mediate the beneficial effects of HDAC inhibitors (HDACi) in mdx mice. We found that the phenotype adopted by these cells and their biological activity are influenced by changes in muscle environment. While Sca1-positive muscle interstitial cells from healthy muscles spontaneously adopt a fibro-adipogenic phenotype, Sca1-positive muscle interstitial cells isolated from dystrophic muscles of young mdx mice show a latent myogenic phenotype that is implemented by the exposure to HDACi. Co-culture assays in vitro and co-transplantation experiments in vivo demonstrate that HDACi also improve Sca1-positive muscle interstitial cell ability to enhance the differentiation potential of adjacent satellite cells. Importantly, HDACi-induced myogenic phenotype and pro-regeneration activity were not observed in Sca1-positive muscle interstitial cells isolated from muscles of old mdx mice. The different phenotype of Sca1-positive muscle interstitial cells from mdx mice at different stages of disease progression correlated with the stage-dependent beneficial effect of HDACi, which were effective only at early stages of disease. Transplantation of Sca1-positive muscle interstitial cells isolated from regenerating young muscles into muscles of old mdx mice restored HDACi ability to increase myofiber size. These results indicate that Sca1-positive muscle interstitial cells are key cellular determinants of disease progression and mediate the beneficial effect of HDACi in a mouse model of muscular dystrophy. Isolation of Sca1+ muscle interstitial cells from TSA treated DMD/MDX mice and MuSc from DMD/MDX mice
2012-03-31 | E-GEOD-34843 | biostudies-arrayexpress
Project description:Duchenne muscular dystrophy (DMD) is caused by an out-of-frame mutation in the DMD gene that results in the absence of a functional dystrophin protein, leading to a devastating and progressive lethal muscle-wasting disease. Genetic modifiers have been shown to increase disease severity in DMD mouse models as well as in human patients. Little is known about cellular heterogeneity in skeletal muscle as disease severity increases. To address this, we explored skeletal muscle-resident cell populations in healthy (wt-NSG), dystrophic (mdx-NSG), and severely dystrophic (mdxD2-NSG) mouse models utilizing scRNA-seq. We found an increased frequency of activated fibroblasts, activated fibro-adipogenic progenitor cells, and proinflammatory macrophages in dystrophic and severely dystrophic gastrocnemius muscles. Moreover, in endothelial cells we found an upregulation of extracellular matrix and platelet aggregation genes in dystrophic and severely dystrophic muscles, indicating endothelial cell functional impairment. In summary, this work extends the understanding of the severe nature of DMD, which should be considered when developing regenerative therapeutic avenues for DMD.
2022-09-27 | GSE213925 | GEO
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
Project description:Duchenne muscular dystrophy (DMD) is a progressive severe muscle-wasting disease caused by mutations in DMD encoding dystrophin that leads to loss of muscle function with cardiac/respiratory failure and premature death. Since dystrophic muscles are sensed by infiltrating inflammatory cells and gut microbial communities can cause immune dysregulation and metabolic syndrome, we sought to investigate whether intestinal bacteria may support the muscle immune response in mdx dystrophic animal model. We assess this question here through unbiased profiling of muscle transcriptome through RNAseq. We found that the absence of gut microbes through the generation of a mdx GF animal model as well as modulation of the microbial community structure by antibiotic treatment revealed the ability of the dystrophic-associated intestinal microbiota to modulate immunity and secondary muscle pathogenetic mechanisms of DMD, including inflammation, fibrosis, and atrophy.
2022-11-22 | GSE218370 | GEO
Project description:Pathophysiology of Duchenne Muscular Dystrophy (DMD) is still elusive. Although progressive damage to muscle fibres is a cause of muscle deterioration leading to premature death, there is a growing body of evidence indicating that the triggering effects of DMD mutation are present at the very early stage of muscle development. To study this, we have performed an RNA-seq experiment to compare the transcriptional profile of early stage myoblasts from dystrophic mice compared to WT mice. We have used a myoblast cell line carrying the mdx mutant allele (SC5), which results in a premature stop codon in the Dystrophin gene, leading to a dystrophic phenotype. The WT cell line is the IMO myoblast cell line.
2019-10-02 | E-MTAB-7287 | biostudies-arrayexpress
Project description:Duchenne muscular dystrophy (DMD) is a debilitating and typically fatal X-linked progressive neuromuscular disorder that results in progressive muscle degeneration aggravated by sterile inflammation. The P2RX7 purinoceptor is an extracellular ATP-gated ion channel expressed in immune cells, and has been targeted in treatment of infectious and inflammatory diseases. In particular, P2xr7 receptor abnormalities have been demonstrated in mdx dystrophic mice, a model for DMD lacking expression of the full length dystrophin transcript through a single point mutation in exon 23. Here, we looked at the differential effects in gene expression regulation in whole muscle in dystrophic mdx mice with or without ablation of the P2rx7 purinoceptor.
2019-09-26 | E-MTAB-7698 | biostudies-arrayexpress