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

ABSTRACT: 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.

ORGANISM(S): Mus musculus

PROVIDER: GSE268313 | GEO | 2025/01/02

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

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