Targeting STAT6 to mitigate sepsis-induced muscle atrophy and weakness: Modulation of mitochondrial dysfunction, ferroptosis, and CHI3L1-Mediated satellite cell loss.
Biochem Biophys Rep
; 37: 101608, 2024 Mar.
Article
en En
| MEDLINE
| ID: mdl-38188367
ABSTRACT
Sepsis-induced muscle weakness is a debilitating consequence of prolonged critical illness, often associated with a poor prognosis. While recent research has shown that STAT6 functions as an inhibitor of myogenesis, its role in sepsis-induced muscle weakness remains unclear. In this study, we hypothesized that inhibiting STAT6 could attenuate sepsis-induced muscle atrophy and weakness, and we explored the underlying mechanisms. Leveraging a microarray dataset from sepsis patients, we identified significant enrichment of genes related to muscle function, ferroptosis, and the p53 signalling pathway in muscle tissue from sepsis patients. Using a murine sepsis model induced by cecum ligation and puncture (CLP), we explore the multifaceted role of STAT6 inhibition. Our findings demonstrate that STAT6 inhibition effectively attenuates muscle atrophy, enhances grip strength, preserves mitochondrial integrity, and modulates ferroptosis in septic mice. Additionally, we identify elevated levels of CHI3L1 in septic muscle tissue, which are significantly reduced by STAT6 inhibition. In-depth analysis of primary muscle satellite cells reveals that CHI3L1 overexpression is associated with increased expression of key regulators of satellite cell myogenicity, while negatively impacting cell viability. Silencing CHI3L1 expression mitigates satellite cell injury and loss, highlighting its pivotal role in sepsis-induced muscle damage. In summary, this study unveils the potential of STAT6 as a therapeutic target for mitigating sepsis-induced muscle atrophy and weakness. Our findings underscore the regulation of mitochondrial dysfunction, ferroptosis, and CHI3L1-mediated satellite cell damage by STAT6, offering promising avenues for therapeutic intervention in the management of sepsis-induced muscle weakness.
Texto completo:
1
Colección:
01-internacional
Base de datos:
MEDLINE
Tipo de estudio:
Prognostic_studies
Idioma:
En
Revista:
Biochem Biophys Rep
Año:
2024
Tipo del documento:
Article
País de afiliación:
China