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lncRNA MALAT1 Accelerates Skeletal Muscle Cell Apoptosis and Inflammatory Response in Sepsis by Decreasing BRCA1
Hui Yong1, Gangming Wu2, Jingyuan Chen2
1Department of Anesthesiology, The First Affiliated Hospital of Southwest Medical University, Luzhou 646000, P.R. China.
Abstract:
Sepsis is a serious and elusive syndrome caused by infection, which is accompanied by a high mortality worldwide. Recent evidence has documented the regulatory role of long non-coding RNA (lncRNA) metastasis-associated lung adenocarcinoma transcript 1 (MALAT1) during the inflammatory process, the effects of which in the development of sepsis have become the focus of the current study. An in vivo mouse model and in vitro cell model of sepsis induced by lipopolysaccharide (LPS) were developed. High expression of lncRNA MALAT1 along with low expression of breast cancer susceptibility gene 1 (BRCA1) were identified in septic mice and human skeletal muscle cells of sepsis. Then, lncRNA MALAT1 expression was altered in vivo and in vitro to examine serum levels of inflammatory factors, as well as skeletal muscle cell apoptosis. lncRNA MALAT1 was noted to regulate the expression and export from the nucleus of BRCA1 by recruiting zeste homolog 2 (EZH2) in skeletal muscle cells of sepsis. Silencing lncRNA MALAT1 resulted in reduced serum levels of interleukin (IL)-6, IL-8, and tumor necrosis factor alpha (TNF-α), neutrophil migration, skeletal muscle cell apoptosis, and AKT-1 phosphorylation. Taken together, lncRNA MALAT1 interacting with EZH2 stimulated AKT-1 phosphorylation and decreased BRCA1 expression, consequently aggravating the progression of sepsis, highlighting a promising therapeutic option for sepsis.
Insights
Long non-coding RNA MALAT1 exacerbates sepsis by decreasing BRCA1 expression and increasing inflammation. Silencing MALAT1 reduced sepsis progression, offering a potential therapeutic target.
Area of Science:
- Molecular Biology
- Immunology
- Genetics
Background:
- Sepsis is a life-threatening condition with high mortality.
- Long non-coding RNAs (lncRNAs) play a role in inflammatory processes.
- The role of lncRNA MALAT1 in sepsis development requires further investigation.
Purpose of the Study:
- To investigate the role of lncRNA MALAT1 in sepsis.
- To explore the mechanism by which MALAT1 influences sepsis progression.
- To evaluate MALAT1 as a potential therapeutic target for sepsis.
Main Methods:
- Established in vivo mouse and in vitro cell models of sepsis induced by lipopolysaccharide (LPS).
- Measured expression levels of lncRNA MALAT1 and BRCA1 in septic models.
- Manipulated MALAT1 expression to assess its effects on inflammatory factors, neutrophil migration, and skeletal muscle cell apoptosis.
Main Results:
- High expression of lncRNA MALAT1 and low expression of BRCA1 were observed in sepsis.
- MALAT1 regulates BRCA1 expression and nuclear export by recruiting EZH2.
- Silencing MALAT1 reduced inflammatory cytokine levels (IL-6, IL-8, TNF-α), neutrophil migration, skeletal muscle cell apoptosis, and AKT-1 phosphorylation.
Conclusions:
- lncRNA MALAT1 interacts with EZH2, promoting AKT-1 phosphorylation and decreasing BRCA1 expression.
- This interaction aggravates sepsis progression.
- lncRNA MALAT1 represents a promising therapeutic target for sepsis management.
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