Long Non-Coding RNA MALAT1 Accelerates Skeletal Muscle Cell Apoptosis and Inflammatory Response in Sepsis Through Decreasing BRCA1 Expression by Recruiting EZH2

Abstract

Background: Sepsis is a serious and elusive syndrome caused by infection, which is accompanied by a high rate of mortality worldwide. Studies have speculated the role of long non-coding RNAs (lncRNAs) in sepsis. However, the potential role of metastasis-associated lung adenocarcinoma transcript 1 (MALAT1) in sepsis is largely unknown. Thus, the present study intended to investigate the possible role of MALAT1 in relation to the development of sepsis and to explore the underlying mechanism. Methods: In vivo mouse model and in vitro cell model of sepsis induced by lipopolysaccharide (LPS) were constructed. Then in order to evaluate the effect of MALAT1 on the progression of sepsis, the expression of MALAT1 was silenced in sepsis mice, followed by the measurement of number of neutrophils in peripheral blood, serum levels of inflammatory factors, as well as skeletal muscle cell apoptosis. Furthermore, interactions among MALAT1, EZH2 and BRCA1 and the regulatory role of MALAT1/EZH2 on sepsis were determined in skeletal muscles cells of sepsis. Results: High expression of MALAT1 along with low expression of BRCA1 was detected in sepsis. MALAT1 was observed to regulate the expression and nucleation of BRCA1. Silencing MALAT1 resulted in reduced serum levels of IL-6, IL-8 and TNF-α, neutrophil migration, skeletal muscle cell apoptosis, number of EZH2 positive cells, extent of AKT-1 phosphorylation along with stimulated BRCA1 expression. Furthermore, MALAT1 regulated the expression and localization of BRCA1 by recruiting EZH2. Conclusion: Taken together, the key observations of the study provide evidence that 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. Funding Statement: This study was supported by the National Natural Science Foundation of China (No. 81772128). Declaration of Interests: The authors have declared that no competing interests exist. Ethics Approval Statement: All animal experiment protocols were approved by the Animal Care Committee of The First Affiliated Hospital of Southwest Medical University and were in compliance with the guidelines established by the Guide for the Care and Use of Laboratory Animals.