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Spatial transcriptomics and scRNA-sequencing on gastrocnemius muscle form B6-mdx and D2-mdx mice

ABSTRACT: We investigated the cell-type composition of muscle domains that associate with muscle degeneration severity in two mouse models of human DMD, namely the B6.mdx and D2.mdx. We first combined immunofluorescence-based histological analysis and spatial transcriptomics to highlight specific muscle tissue clusters that display dystrophic features with necrotic fibers, inflammatory cell infiltration and increased fibrosis. Using single-cell RNA-sequencing reference and spatial deconvolution, we profiled cell types and states within each dystrophic domain, thereby identifying the enrichment for specific cell subpopulations in these spatial clusters.

ORGANISM(S): Mus musculus

PROVIDER: GSE297388 | GEO | 2026/07/01

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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Spatial transcriptomics and scRNA-sequencing on gastrocnemius muscle form B6-mdx and D2-mdx mice

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