The FSHD effector protein Dux promotes myopathy via Myostatin-Smad signaling
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ABSTRACT:
PROVIDER: PRJNA428752 | ENA |
REPOSITORIES: ENA
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Project description:Facioscapulohumeral muscular dystrophy (FSHD) is an autosomal-dominant condition that is characterised by a progressive degeneration and weakness of skeletal muscle fibers. The underlying cause of FSHD has been attributed to inappropriate expression of the transcription factor double homeobox (Dux); however, the mechanisms leading to myopathy in response to Dux expression remain incompletely understood. To study the acute effects of Dux activation in mammalian skeletal muscle fibers, we generated a recombinant adeno-associated viral vector allowing tunable Dux expression. Consistent with previous findings, we confirmed that the ectopic expression of Dux in mouse skeletal muscle results in a degenerative myopathy. Building on these findings, we observed that the acute expression of Dux in muscle fibers causes profound transcriptome changes prior to the onset of pathology. Furthermore, muscles expressing Dux display elevated levels of the TGF-beta superfamily member, Myostatin and increased Smad2/3 activity. Notably, inhibition of Myostatin is sufficient to prevent Dux-induced myopathy. Collectively, these findings support further investigation of interventions targeting the Myostatin-Smad2/3 pathway as prospective approaches to treating myopathy associated with Dux mis-expression.
2021-12-31 | GSE108828 | GEO
Project description:Facioscapulohumeral muscular dystrophy (FSHD) is an autosomal dominant disorder linked to contractions of the D4Z4 repeat array in the subtelomeric region of chromosome 4q. By comparing genome-wide gene expression data from muscle biopsies of patients with FSHD to those of 11 other neuromuscular disorders, we intend to identify disease-specific changes which are more likely to be involved in the early stages of the disease progression. The data will help to identify pathological mechanisms involved in FSHD. Experiment Overall Design: Comparison of the profiles of FSHD to 13 other conditions for disease-specific changes. The 13 conditions are NHM (Normal healthy muscle) n=15; JDM (Juvenile dermatomyositis) n=25; HSP (Human spastic paraplegia) n=4; FSHD (facioscapulohumeral dystrophy) unaffected n=5, affected n=9; FKRP (Fukutin related protein deficiency) n=7; ED-L (Emery-Dreifuss muscular dystrophy, lamin A/C deficiency) n=4; ED-E (Emery-Dreifuss muscular dystrophy, emerin deficiency) n=4; DYSF (dysferlinopathy) n=10; DMD (Duchenne Muscular Dystrophy) n=10; CALP (Calpain-3 deficiency) n=10; BMD (Becker Muscular Dystrophy) n=5; AQM (Acute quadriplegic myopathy) n=5; ALS (Amyotrophic lateral sclerosis) n=9.
2008-06-16 | E-GEOD-9397 | biostudies-arrayexpress
Project description:DUX4 and its mouse ortholog Dux are normally expressed in the early embryo—the 4 cell or 2 cell cleavage stage embryo, respectively—and activate a portion of the first wave of zygotic gene expression. DUX4 is epigenetically suppressed in nearly all somatic tissue, whereas FSHD-causing mutations result in its aberrant expression in skeletal muscle, transcriptional activation of the early embryonic program, and subsequent muscle pathology. Although DUX4 and Dux both activate an early totipotent transcriptional program, divergence of their DNA binding domains limits the use of DUX4 expressed in mice as a pre-clinical model for FSHD. In this study, we identify the porcine DUXC mRNA expressed in early development and show that both pig DUXC and human DUX4 robustly activate a highly similar early embryonic program in pig muscle cells. These results support further investigation of pig preclinical models for FSHD.
2023-05-10 | GSE210772 | GEO
Project description:We report both DUX4 and Dux toxicity depend upon their ability to bind DNA and activate transcription. Chromatin immunoprecipitation of V5 epitope tagged human DUX4 and mouse Dux was performed in human myoblasts was analyzed using ChIP-Seq to identify their subsequent binding sites. We found that DUX4 and Dux bind 4-8% of identical sequences, while majority of the binding sites are unique to either DUX4 or Dux. Although small, this overlap could be due to their conserved abilioty to regualte primordial pathways that were essential for life and therefore maintained in both proteins despite their separate evolutionary paths. We performed ChIP-Seq analysis of human myoblasts transfected with plasmids encoding either epitope tagged human DUX4 (1 sample) and mouse Dux (1 sample). Illumina sequencing libraries were prepared from the ChIP and Input DNA, then resulting DNA libraries were quantified and sequenced and aligned to the human genome (hg19).
2015-12-11 | E-GEOD-75791 | biostudies-arrayexpress
Project description:We report the RNA-seq experiments performed in human myoblasts transfected with human DUX4 and mouse Dux. Comparison of genes up- and down-regulated by DUX4 and Dux in human myoblasts to identify pathways similiarly regulated by both transcription factors.
2016-08-24 | E-GEOD-85935 | biostudies-arrayexpress
Project description:Background: The aim of this study is to improve our understanding of the mechanisms underlying the sparing of masticatory muscles in ICU patients with acute quadriplegic myopathy (AQM) by using a unique porcine ICU model, i.e., 5-day longitudinal experiments where animals are sedated, mechanically ventilated and exposed to factors triggering AQM, such as muscle unloading, endotoxin-induced sepsis, and systemic exposure to CS and NMBA. Results: An increased expression was notably observed in atrogin-1, cathepsins, FoxO1a, runx1 and heat-shock proteins genes. A decreased expression in some sarcomeric proteins and myostatin genes was also noticed. Hence, modifications in heat-shock proteins and myostatin genes are in sharp contrast to alterations in the limb muscles and it is postulated that elevated heat-shock proteins and decreased myostatin genes play a protective role in the masticatory muscle in ICU patients with AQM. Conclusions: We have observed a general down-regulation of muscle proteins and myostatin. Genes involved in the UPS system, cathepsins, RUNX1, TBX1, TIMP2 and transcripts of heat-shock proteins were up-regulated. However, we have neither observed a decrease in fiber CSA or force generation, suggesting that the expected atrophic changes have been countered by a protective mechanism and myostatin downregulation. Five female domestic piglets were treated with non-depolarizing neuromuscular blocking agents (NMBA), corticosteroids(CS) and sepsis. Five female piglets were untreated.
2010-09-21 | E-GEOD-24239 | biostudies-arrayexpress
Project description:To determine whether DUX domain binding to SMARCC1 influence chromatin reodeling at DUX binding sites, we performed ATAC-seq We know DUX binding sites are open at the time of expression, but we do not know which domains are required to be present with the discovery of the C-terminal repeats and 14 amino acid tail
2023-08-07 | GSE224298 | GEO
Project description:Facioscapulohumeral muscular dystrophy (FSHD) is an autosomal dominant disorder linked to contractions of the D4Z4 repeat array in the subtelomeric region of chromosome 4q. By comparing genome-wide gene expression data from muscle biopsies of patients with FSHD to those of 11 other neuromuscular disorders, we intend to identify disease-specific changes which are more likely to be involved in the early stages of the disease progression. The data will help to identify pathological mechanisms involved in FSHD. Keywords: Differentiation design
2007-10-23 | GSE9397 | GEO
Project description:Inhibition of myostatin signaling induces strong skeletal muscle growth making it an attractive target to treat muscle wasting and sarcopenia. However, the biological function of myostatin in the heart is barely understood. We demonstrate that conditional inactivation of myostatin in the adult murine heart leads to cardiac hypertrophy, heart failure and increased lethality. To induce cardiomyocyte specific loss of myostatin a conditionally active Mstn^fl/fl allele was generated by insertion of loxP elements upstream and downstream of exons 1 and 2 of the mouse myostatin gene. The selection cassette was removed in vivo by flp-recombination. To inactivate myostatin, mice were mated to alphaMyHC-MCM mice (Sohal, DS, et al. (2001) Circulation Research 89, 20-25). Cre-recombination was achieved by intraperitoneal administration of Tamoxifen (40 mg/kg) for 5 consecutive days. The respective control alphaMyHC-MCM animals were equally treated.
2014-05-16 | E-MEXP-3744 | biostudies-arrayexpress
Project description:To identify microRNAs involved in myostatin-deficient muscular hypertrophy, we compared miRNA expression in wild-type and myostatin knockout mice.
2013-12-17 | GSE49523 | GEO