RNA-seq comparison of whole muscle between WT mice, dystrophic mice, and P2rx7-null dystrophic mice
Ontology highlight
ABSTRACT:
INSTRUMENT(S): Illumina HiSeq 2500
ORGANISM(S): Mus musculus
SUBMITTER: Sam Robson
PROVIDER: E-MTAB-7698 | biostudies-arrayexpress |
REPOSITORIES: biostudies-arrayexpress
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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.
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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 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.
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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.
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Project description:Fibro-adipogenic progenitors (FAPs) are emerging cellular components of the skeletal muscle regenerative environment. The alternative functional phenotype of FAPs - either supportive of muscle regeneration or promoting fibro-adipogenic degeneration M-bM-^@M-^S is a key determinant in the pathogenesis of muscular diseases, including Duchenne Muscular Dystrophy (DMD). However, the molecular regulation of FAPs is still unknown. We show here that an M-bM-^@M-^\HDAC-myomiR-BAF60 variant networkM-bM-^@M-^] regulates the functional phenotype of FAPs in dystrophic muscles of mdx mice. Combinatorial analysis of gene expression microarray and genome-wide chromatin remodeling by Nuclease accessibility (NA)-seq revealed that HDAC inhibitors de-repress a M-bM-^@M-^\latentM-bM-^@M-^] myogenic program in FAPs from dystrophic muscles at early stages of disease progression. In these cells HDAC inhibition promoted the expression of two core components of the myogenic transcriptional machinery, MyoD and BAF60C, and upregulated the myomiRs (miRs) 1.2, 133 and 206, which target two alternative BAF60 variants (BAF60A and B) ultimately leading to the activation of a pro-myogenic program at the expense of the fibro-adipogenic phenotype. By contrast, FAPs from dystrophic muscles at late stages of disease progression displayed resistance to HDACi-induced chromatin remodeling at myogenic loci and fail to activate the pro-myogenic phenotype. These results reveal a previously unappreciated disease stage-specific bipotency of mesenchimal cells within the regenerative environment of dystrophic muscles. Resolution of such bi-potency by epigenetic interventions, such as HDACi, provides the molecular rationale for the in situ reprogramming of target cells to promote therapeutic regeneration of dystrophic muscles. Genome-wide chromatin accessibility patterns in FAPs cells derived from mdx mice at different ages treated either with HDAC inhibitor Trichostatin A (TSA) or with vehicle (saline solution) were assessed using NA-seq (PMID: 19289091)
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