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Inflammation in a severe model of dystrophic cardiomyopathy contains a high proportion of T-cells that contribute to onset of pathology

ABSTRACT: Duchenne muscular dystrophy (DMD) is a severe neuromuscular disorder characterized by progressive muscle degeneration and cardiomyopathy leading to heart failure. While the inflammatory environment in dystrophic skeletal muscle has been well-studied, little is known about inflammation in the progression of DMD cardiomyopathy due to the lack of adequate animal models. To address this, we developed the Fiona/dko mouse model, which exhibits severe, isolated dystrophic cardiomyopathy. In this study, we used Fiona/dko mice to characterize the immune cell composition in dystrophic heart and investigated the contribution of T-cells to the onset and progression of cardiac pathology. Flow cytometry analysis revealed that T-cells constitute a significant proportion of the immune cell population in Fiona/dko hearts, in contrast to the predominantly myeloid signature observed in dystrophic skeletal muscle. Furthermore, we demonstrated that T-cell infiltration precedes the development of cardiac fibrosis and dysfunction in Fiona/dko mice and that depletion of circulating CD3+ T-cells ameliorates early pathology, suggesting a role for T-cells in the initiation and persistence of dystrophic cardiomyopathy. These findings highlight the distinct inflammatory environment in the dystrophic heart and provide new insights into the pathogenesis of DMD cardiomyopathy, paving the way for the development of targeted anti-inflammatory therapies.

ORGANISM(S): Mus musculus

PROVIDER: GSE276884 | GEO | 2025/12/26

REPOSITORIES: GEO

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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.

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Inflammation in a severe model of dystrophic cardiomyopathy contains a high proportion of T-cells that contribute to onset of pathology

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