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STAT3 Regulates Adult Muscle Satellite Cell Maintenance During Injury-induced Muscle Regeneration

ABSTRACT: We previously showed that STAT3 regulates myoblast differentiation in cell culture models, yet its role in adult muscle satellite cells (MuSC) in vivo was less well characterized. When Stat3 was conditionally deleted in MuSC, muscle development and adult MuSC formation were not affected. However, with repeated muscle injuries, the number of the quiescent MuSC in STAT3-null mice decreased and the regeneration was delayed, suggesting defective MuSC maintenance. Consistently, when we conditionally deleted Stat3 in MuSC of dystrophin-null mice, a mouse model for the fatal human Duchenne muscular dystrophy, the adult double knockout (dKO) mice displayed age-dependent reduction in the number of MuSC, and increase in muscle inflammation and fibrosis. Mechanistically, Stat3 ablation in dystrophin-null MuSC resulted in downregulation of several key myogenic genes including Pax7, upregulation of multiple pro-inflammatory and pro-fibrotic genes, and an increase in fibroadipogenic progenitor cells, which collectively contributed to defective MuSC maintenance and aggravated inflammation and fibrosis in dKO mice.

ORGANISM(S): Mus musculus

PROVIDER: GSE68736 | GEO | 2016/07/13

SECONDARY ACCESSION(S): PRJNA283532

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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STAT3 Regulates Adult Muscle Satellite Cell Maintenance During Injury-induced Muscle Regeneration

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