Dataset Information

Nox4 inhibitor treatment ameliorates cardiac function in mouse models of Duchenne Muscular Dystrophy

ABSTRACT: Duchenne Muscular Dystrophy (DMD) is caused by mutations in dystrophin, leading to degeneration and weakness of the skeletal and cardiac muscles. Despite numerous efforts in developing therapies for this devastating disease, DMD remains a fatal disease. Our recent study showed that loss of the cardiac Isl1-interacting protein (CIP), which interacts with dystrophin in sarcolemma of cardiomyocytes, accelerates the progression of dystrophic cardiomyopathy. We identified Nox4 as one of the downstream mediators of this process. Here, we report that Setanaxib, a Nox1/4 inhibitor, protected the heart of CIP/Mdx double knockout (dKO) mice from heart failure and reduced cardiac fibrosis. Similarly, Setanaxib treatment exhibited lower cardiac fibrosis and protection against heart failure in Mdx/Utrn dKO mouse, another murine model for dystrophic cardiomyopathy. Additionally, treatment with Nox4 inhibitor reduced the expression of cardiomyopathy genes in dystrophic mice. Interestingly, transcriptomic analysis of the hearts from Mdx/Utrn dKO mice treated with Nox4 inhibitor reveals an enrichment of genes associated with fatty acid metabolism, oxidative phosphorylation, and protein binding, while genes related to inflammation and epithelial-mesenchymal transition were downregulated. Consistent with these results, we found increased expression of Pgc1a and Tcap in the hearts of Mdx/Utrn dKO mice treated with Nox 4 inhibitor, and reduced expression of Mcp1. Collectively, these findings suggest that Nox4 plays a key role in development of myocardial fibrosis and heart failure caused by dystrophin deficiency, and suggest that Nox4 inhibition could be a potential novel therapy to alleviate cardiomyopathy in DMD patients.

ORGANISM(S): Mus musculus

PROVIDER: GSE310316 | GEO | 2025/11/18

REPOSITORIES: GEO

ACCESS DATA

Dataset's files

Source:

			Action	DRS
		Other

Items per page:

1 - 1 of 1

Similar Datasets

Project description:Duchenne muscular dystrophy (DMD) is characterized by impaired cytoskeleton organization, cytosolic calcium handling oxidative stress and mitochondrial dysfunction. This results in progressive and fatal muscle damage, wasting and weakness. The Striated Muscle activator of Rho signalling (STARS) is an actin binding protein that activates the myocardin-related transcription factor-A (MRTFA)/serum response factor (SRF) transcriptional pathway; a pathway that regulates cytoskeletal structure, muscle function, growth and repair. Here we investigated the regulation of several members of the STARS signalling pathway in muscle from patients with DMD and the dystrophin-deficient mdx and dko (utrophin‐ and dystrophin‐null) mice. A reduction in protein levels of STARS, SRF and RHOA, and an increase in MRTFA were observed in quadriceps muscle of patients with DMD. STARS, SRF and MRTFA mRNA levels were also decreased in DMD muscle, while Stars mRNA levels were decreased in mdx tibialis anterior (TA) muscle and Srf and Mrtfa mRNAs were decreased in dko TA muscle. Overexpressing the human STARS (hSTARS) protein in mdx TA muscle increased maximal isometric specific force by 13%. This was not associated with changes in muscle mass, fibre cross-sectional area (CSA), fibre type, centralized nuclei or collagen deposition. Proteomics screening identified 31 upregulated and 22 downregulated proteins or individual peptides that were significantly regulated by hSTARS overexpression. Pathway enrichment analysis indicated that hSTARS overexpression regulated the keratin, NRF2 and oxidative phosphorylation (OXPHOS) pathways. These pathways are impaired in dystrophic muscle and regulate cytoskeleton organization, oxidative stress and mitochondrial energy production; processes that are vital for muscle function. We conclude that increasing the STARS protein in dystrophic muscle improves muscle force production, potentially via its regulation of multiple pathways that positively influence cytoskeletal structure, oxidative stress and energy production.

Dataset Information

Nox4 inhibitor treatment ameliorates cardiac function in mouse models of Duchenne Muscular Dystrophy

Dataset's files

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets