Effects of Pten knockout in dystrophic skeletal muscles of mdx mouse
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ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE150220 | GEO | 2020/10/06
REPOSITORIES: GEO
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Project description:Effects of Pten knockout in dystrophic skeletal muscles of mdx mouse
| PRJNA631535 | ENA
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:The mdx mouse (C57BL/10ScSn-DMDmdx/J), like Duchenne muscular dystrophy (DMD) patients, lacks the protein dystrophin. However, the mdx mouse has a normal lifespan and mild pathology while DMD remains a severe, fatal disease. New mouse models have been developed that are more severely affected but they have not replaced the mdx mouse in DMD research. A few years ago RNA-sequencing (RNA-seq) results of biopsies from DMD and normal human muscle were published but we could not find equivalent data for the mouse. We now report RNA-sequencing of three wild-type and mdx mouse muscles: the flexor digitorum brevis (FDB), the extensor digitorum longus (EDL), and the soleus (SOL). The FDB, a plantar foot muscle is often used for in vivo and ex vivo experiments but may be less affected by the lack of dystrophy than the hindlimb muscles. We compared muscles from 2- and 5-month old mice to investigate the time-course of the mdx pathology. The results show a muscle- and age-dependent parallel between mdx and DMD muscles. Although the FDB is less affected than EDL and SOL at 2 months, the three muscles show, at both ages, activation of close to 100 genes from 7 pathways that are affected in presymptomatic DMD patients and have been called "DMD disease signature".
2021-06-22 | GSE162455 | GEO
Project description:Duchenne muscular dystrophy (DMD) is an X-linked recessive disease caused by deleterious mutations in the DMD gene, rendering non-functional forms or complete absence of the protein dystrophin. Eccentric contraction-induced force loss is the most robust and reproducible phenotype of dystrophin-deficient skeletal muscle, yet the molecular mechanisms underlying force loss remain obscure. To this end, we utilized the mdx mouse model of DMD, which displays extreme sensitivity to eccentric contractions. An existing mouse line from our lab that overexpresses cytoplasmic gamma-actin specifically in skeletal muscle (mdx/Actg1-TG) was shown to significantly protect mdx muscle against contraction-induced force loss. To understand the mechanism behind this protection, we performed iTRAQ proteomics on mdx/Actg1-TG tibialis anterior (TA) muscle versus non-transgenic littermate controls to identify differentially-expressed proteins that may afford protection upon gamma-actin overexpression.
2018-10-22 | PXD009680 | Pride
Project description:RNA-seq was performed to compare expression pattern of musles taken form two mice strains- mdx and mdx/Runx1f/f, which are double KO carrting a muscle specific ablation of Runx1 using a Myf5-Cre. This comparison revealed the Runx1- responsive gene set in mdx muscles. we could cross this data with prior retrived datd from privous experiments found in this GEO quary, to pinpiont Runx1 target genes in muscle rgeneration
2015-08-17 | GSE68998 | GEO
Project description:Pharmacological treatment of Duchenne Muscular Dystrophy (DMD) with histone deacetylase inhibitors (HDACi) is currently being tested in clinical trials. Pre-clinical studies performed in mdx mice - the mouse model of DMD - have shown that HDACi promote compensatory muscle regeneration, while inhibiting fibro-adipogenic degeneration, by targeting fibro-adipogenic progenitors (FAPs); however, these beneficial effects are restricted to early stages of disease progression. We show here that FAPs from late stage mdx mice exhibit epigenetic and transcriptional features of senescence that could not be fully reversed by HDACi. In particular, genome-wide increase in H3K9/14 acetylation at gene promoters of Senescence Associated Secretory Phenotype (SASP) genes was associated with their upregulation in late stage mdx FAPs. Treatment with the HDACi Trichostatin A (TSA) could inhibit SASP gene activation in FAPs, by decreasing H3K9/14 acetylation. Conversely, combinatorial decrease of H3K27 and/or H3K9/14 acetylation at promoters of genes required for cycle activation and progression was associated with their downregulation in FAPs from late stage mdx mice. However, these epigenetic and transcriptional alterations could not be reversed by TSA, due to a general resistance exhibited by FAPs from late stage mdx mice to HDACi-induced H3K9/14 hyperacetylation. Overall, this data reveal that disease-associated features of senescence develop in FAPs of DMD muscle through epigenetically distinct and pharmacologically dissociable events, and suggests that HDACi might at least retain anti- fibrotic and inflammatory activity at late stages of DMD, by repressing FAP-derived SASP.
2022-02-01 | GSE189823 | GEO
Project description:Pharmacological treatment of Duchenne Muscular Dystrophy (DMD) with histone deacetylase inhibitors (HDACi) is currently being tested in clinical trials. Pre-clinical studies performed in mdx mice - the mouse model of DMD - have shown that HDACi promote compensatory muscle regeneration, while inhibiting fibro-adipogenic degeneration, by targeting fibro-adipogenic progenitors (FAPs); however, these beneficial effects are restricted to early stages of disease progression. We show here that FAPs from late stage mdx mice exhibit epigenetic and transcriptional features of senescence that could not be fully reversed by HDACi. In particular, genome-wide increase in H3K9/14 acetylation at gene promoters of Senescence Associated Secretory Phenotype (SASP) genes was associated with their upregulation in late stage mdx FAPs. Treatment with the HDACi Trichostatin A (TSA) could inhibit SASP gene activation in FAPs, by decreasing H3K9/14 acetylation. Conversely, combinatorial decrease of H3K27 and/or H3K9/14 acetylation at promoters of genes required for cycle activation and progression was associated with their downregulation in FAPs from late stage mdx mice. However, these epigenetic and transcriptional alterations could not be reversed by TSA, due to a general resistance exhibited by FAPs from late stage mdx mice to HDACi-induced H3K9/14 hyperacetylation. Overall, this data reveal that disease-associated features of senescence develop in FAPs of DMD muscle through epigenetically distinct and pharmacologically dissociable events, and suggests that HDACi might at least retain anti- fibrotic and inflammatory activity at late stages of DMD, by repressing FAP-derived SASP.
2022-02-01 | GSE189824 | GEO
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
Project description:ABSTRACT Stimulating the commitment of implanted dystrophin+ muscle derived stem cells (MDSC) into myogenic, as opposed to lipofibrogenic, lineages is a promising therapeutic strategy for Duchenne muscular dystrophy (DMD). To examine whether counteracting myostatin, a negative regulator of muscle mass and a pro-lipofibrotic factor, would help this process, we compared the in vitro myogenic and fibrogenic capacity of MDSC from wild type (WT), myostatin knockout (Mst KO), and mdx (DMD model) (mdx) young mice under various modulators, the expression of key stem cell and myogenic genes, and the capacity of these MDSC to repair the injured gastrocnemius in aged mdx mice with exacerbated lipofibrosis. Surprisingly, the potent in vitro myotube formation by WT MDSC was refractory to modulators of myostatin expression or activity, and the Mst KO and mdx MDSC failed to form myotubes under any condition, despite all MDSC expressed Oct-4 and various stem cell genes and differentiated into other lineages. The genetic inactivation of myostatin or dystrophin in MDSC was associated with silencing of critical genes for early myogenesis (Actc1, Acta1, and MyoD). WT MDSC implanted into the injured gastrocnemius of old mdx mice significantly improved myofiber repair and reduced fat deposition and, to a lesser extent, fibrosis. In contrast to their in vitro behavior, Mst KO MDSC in vivo also significantly improved myofiber repair, but had no significant effects on lipofibrotic degeneration. In conclusion, while WT MDSC are considerably myogenic in culture and stimulate muscle repair after injury in the aged mdx mouse, myostatin genetic inactivation blocks myotube formation in vitro but the myogenic capacity is recovered in vivo under the influence of the host tissue environment, presumably by reactivation of key genes originally silenced in the Mst KO MDSC. Key words: dystrophin, mdx mouse, Duchenne, fibrosis, dystrophy One sample each of mouse wild type (WT), myostatin knockout (KO), muscular dystrophy model mdx, and the transgenic OCT4 promoter plus reporter were grown, RNA was isolated, and subjected to the SABiosciences mouse stem cell oligo array.
2012-09-30 | E-GEOD-28986 | biostudies-arrayexpress
Project description:We report that ablation of one SLN allele positively affects mouse mdx DMD heart failure model mice by several metrics including intracellular calcium handling.
2020-11-24 | GSE144596 | GEO