Browse
Submit Data
Databases
API
Help

Dataset Information

0 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

GDF5 modulation of MuSC pool as a potential therapeutic benefit for DMD

ABSTRACT: Duchenne muscular dystrophy (DMD) is a fatal disease characterized by the absence of dystrophin, leading to degeneration of the entire musculature. With the aim of improving muscle pathophysiology and gene therapy for DMD, we investigated the potential of growth differentiation factor 5 (GDF5) in the DMD mdx mouse model. We showed that the overexpression of GDF5 in the muscle improved its histology, reduced inflammation, modulated regeneration and induced the appearance of de novo fibers. We demonstrated that muscle satellite cells (MuSCs) are targeted by GDF5 which enhanced their proliferation and slowed down their myogenic commitment and finally their fusion. Next, we combined GDF5 overexpression with AAV-mediated microdystrophin gene therapy, the most promising treatment for DMD, and showed an increased number of microdystrophin-positive myofibers compared with gene therapy alone. Overall, we reveal here the potential role of GDF5 in improving DMD pathophysiology and provide a first proof of concept of a synergistic effect of the combination of GDF5-based treatment and AAV-microdystrophin.

ORGANISM(S): Mus musculus

PROVIDER: GSE309516 | GEO | 2026/07/29

REPOSITORIES: GEO

ACCESS DATA

Json Xml

Dataset's files

Source:

			Action	DRS
		Other

Items per page:

1 - 1 of 1

Similar Datasets

A Dach2-Hdac9-Myog-Gdf5 signaling system regulates regeneration of neuromuscular synapses

Project description:Muscle denervation due to injury, disease or aging results in impaired motor function. Restoring neuromuscular communication requires axonal regrowth and regeneration of neuromuscular synapses. Muscle activity inhibits neuromuscular synapse regeneration. The mechanism by which muscle activity regulates regeneration of synapses is poorly understood. Dach2 and Hdac9 are activity-regulated transcriptional co-repressors that are highly expressed in innervated muscle and suppressed following muscle denervation. Here, we report that Dach2 and Hdac9 inhibit regeneration of neuromuscular synapses. Importantly, we identified Myog and Gdf5 as muscle-specific Dach2/Hdac9-regulated genes that stimulate neuromuscular regeneration in denervated muscle. Interestingly, Gdf5 also stimulates presynaptic differentiation and inhibits branching of regenerating neurons. Finally, we found that Dach2 and Hdac9 suppress miR206 expression, a microRNA involved in enhancing neuromuscular regeneration. RNAseq on innervated and 3 day denervated adult soleus muscle from wildtype mice is compared with that from 3 day denervated soleus muscle from Dach2/Hdac9 deleted mice to identify Dach2/Hdac9-regulated genes.

2015-10-29 | E-GEOD-58669 | biostudies-arrayexpress

A Dach2-Hdac9-Myog-Gdf5 signaling system regulates regeneration of neuromuscular synapses

2015-10-29 | GSE58669 | GEO

MuSC dysfunction contributes to dystrophic progression and impaired regeneration in the mdx mouse [bulk RNA-seq]

Project description:Duchenne muscular dystrophy (DMD) is a devastating disease characterized by progressive muscle wasting and limitation of life. In addition to the inherent weakness of dystrophin-deficient muscle, the dysfunction of resident muscle stem cells significantly contributes to disease progression. Using the mdx mouse model of DMD, we performed an in-depth characterization of disease progression and muscle stem cell (MuSC) function in dystrophin deficient skeletal muscle using immunohistology, isometric force measurements, transplantation assays, and transcriptomic analysis. Here, we performed bulk RNA-sequencing of wild-type (WT) and mdx myogenic cells in different conditions.

2025-01-02 | GSE268313 | GEO

MuSC dysfunction contributes to dystrophic progression and impaired regeneration in the mdx mouse [scRNA-seq]

Project description:Duchenne muscular dystrophy (DMD) is a devastating disease characterized by progressive muscle wasting and limitation of life. In addition to the inherent weakness of dystrophin-deficient muscle, the dysfunction of resident muscle stem cells significantly contributes to disease progression. Using the mdx mouse model of DMD, we performed an in-depth characterization of disease progression and muscle stem cell (MuSC) function in dystrophin deficient skeletal muscle using immunohistology, isometric force measurements, transplantation assays, and transcriptomic analysis. Here, we performed single cell RNA-sequencing of wild-type (WT) and mdx myogenic cells before and 5-days following cardiotoxin injury.

2025-01-02 | GSE268314 | GEO

Microdystrophins Partially Rescue Duchenne Muscular Dystrophy Deficits in iPSC-Cardiomyocytes

Project description:Duchenne muscular dystrophy (DMD) is a severe muscle wasting disease caused by the lack of dystrophin. Dilated cardiomyopathy is the leading cause of death in DMD patients. Smaller variants of dystrophin, called microdystrophins, amenable to packaging into adeno-associated virus (AAV), have shown to be effective in improving skeletal muscle function in animal models; however, the functional benefit of these microdystrophins in the DMD heart remains unclear. To determine the efficacy of microdystrophin gene therapy, we compared three microdystrophin variants in DMD cardiomyocytes differentiated from human induced pluripotent stem cells (iPSCs). We used three DMD lines of different genetic backgrounds and benchmarked against healthy isogenic controls expressing full-length dystrophin. DMD iPSC-cardiomyocytes exhibit hallmarks of disease, including arrhythmia and poor viability compared to healthy isogenic controls. In parallel, we tested a dystrophin variant, called minidystrophin, which is larger than the microdystrophins. We validated dystrophin expression and compared transcriptional profiles by bulk RNA sequencing. For morphological analysis, we performed immunohistochemistry of cardiac troponin on fixed cells. To test the functional benefit of the transgenes, we performed calcium imaging with a ratiometric calcium indicator as well as viability assays. Our results show that the microdystrophins partially rescue disease phenotypes; however, the results are variable among genetic backgrounds. None of the gene therapies altered the global transcriptional profile of the DMD iPSC-CMs to resemble a healthy profile. Minidystrophin significantly improved cell viability of DMD iPSC-CMs in two of three lines of different genetic backgrounds. Our findings suggest that microdystrophins may have limited efficacy in DMD cardiomyocytes and that the delivery of larger dystrophin variants may be necessary to delay the onset of cardiac complications.

2026-06-30 | GSE310327 | GEO

GDF5 exacerbates tubulointerstitial injury by inducing partial epithelial-mesenchymal transition of tubular epithelial cells in diabetic kidney disease

Project description:Adipokines serve crucial functions in diabetic kidney disease (DKD) pathogenesis. Growth differentiation factor 5 (GDF5) is highly expressed in adipose tissue, but its specific role in DKD is unknown. In this study, we observed elevated GDF5 expression in both DKD patients and db/db mice, suggesting a potential association between GDF5 and DKD progression. Elevated plasma GDF5 levels are associated with an increased risk of incident CKD in patients with type 2 diabetes mellitus. In animal studies, adipose-specific overexpression of GDF5 increased circulating GDF5 and exacerbated renal injury in db/db mice, characterized by increased tubulointerstitial injury and inflammation infiltration. Conversely, adipose-specific knockdown reduced circulating GDF5 and alleviated renal injury. In vitro studies demonstrated that GDF5 induces partial epithelial-mesenchymal transition (pEMT) in renal tubular epithelial cells via activation of the SMAD1/5/8 signaling pathway, as evidenced by reduced E-cadherin expression and increased Snail1 levels. Notably, the supernatant from GDF5-treated injured HK-2 cells was found to enhance the secretion of pro-inflammatory cytokines by macrophages. These findings suggest that adipose-derived GDF5 acts as a novel mediator contributing to tubulointerstitial injury in DKD.

2026-06-30 | GSE301094 | GEO

GDF5-induced tenogenic differentiation of human bone marrow-derived stromal cells (hMSC)

Project description:GDF5 is a potent tenogenic differentiation inducer. We previously demonstrated that GDF5 induced in vitro tenogenesis of human bone marrow-derived stromal cells (hMSC). We used microarrays to detail the global gene expression profiles underlying tenogenesis and identified distinct classes of up-regulated genes during this process.

2017-02-11 | GSE55027 | GEO

scRNAseq RAT DIA WT and DMD 12months

Project description:Duchenne muscular dystrophy (DMD) is a fatal muscle-wasting disorder caused by mutations in the Dystrophin gene with no therapeutic option. To bridge the gap between preclinical and therapeutic evaluation studies, we have generated a rat model for DMD that carries an exon 52 deletion (R DMDdel52) causing a complete lack of dystrophin protein. Here we show that R DMDdel52 animals recapitulated human DMD pathophysiological trajectory more faithfully than the mdx mouse model. We report that R DMDdel52 rats displayed progressive and severe skeletal muscle loss associated with fibrotic deposition, fat infiltration and fibre type switch. Early fibrosis was also apparent in the cardiac muscle. These histological modifications led to severe muscle, respiratory and cardiac functional impairments leading to premature death around one year. Moreover, DMD muscle exhibited systemic inflammation with a mixed M1/M2 phenotype. A comparative single cell RNAseq analysis of the diaphragm muscle was performed, revealing cellular populations alteration and molecular modifications in all muscle cell types. We show that DMD fibroadipogenic progenitors produced elevated levels of cartilage oligomeric matrix protein (COMP), a glycoprotein responsible for modulating homeostasis of extracellular matrix, and whose increased concentration correlated with muscle fibrosis both in R DMDdel52 rats and human patients. Fibrosis is a component of tissue remodelling impacting the whole musculature of DMD patients, at the tissue level but most importantly at the functional level. We therefore propose that this specific biomarker can optimize the prognostic monitoring of functional improvement of patients included in clinical trials.

2022-03-14 | GSE198237 | GEO

Split intein mdx skeletal muscle proteomics

Project description:Duchenne muscular dystrophy is a rare and lethal neuromuscular disease caused by loss-of-function mutations in the dystrophin protein that provides structural integrity to striated muscle fibers. Mice with loss-of-function mutations for the Dmd gene encoding dystrophin (mdx-4cv) were treated with microdystrophin or split-intein AAV constructs to restore various-length dystrophin isoforms to the skeletal muscle compartment. The aim of this study was to compare protein expression profiles between healthy (WT), mdx-4cv, and AAV-treated mdx-4cv gastrocnemius skeletal muscle. We employed an isobaric labeling TMT multiplex discovery proteomics approach to describe and compare proteomic profiles across experimental groups.

2025-11-06 | PXD062324 | Pride