Dataset Information

Excessive expression of miR-1a by statin causes skeletal injury through targeting mitogen-activated protein kinase kinase kinase 1.

ABSTRACT:

Backgrounds

A major side effect of statin, a widely used drug to treat hyperlipidemia, is skeletal myopathy through cell apoptosis. The aim of this study is to investigate the roles of microRNA in statin-induced injury.

Methods

Apolipoprotein E knockout (ApoE-/-) mice were administered with simvastatin (20 mg/kg/day) for 8 weeks. Exercise capacity was evaluated by hanging grid test, forelimb grip strength, and running tolerance test.

Results

In cultured skeletal muscle cells, statin increased the levels of miR-1a but decreased the levels of mitogen-activated protein kinase kinase kinase 1 (MAP3K1) in a time or dose dependent manner. Both computational target-scan analysis and luciferase gene reporter assay indicated that MAP3K1 is the target gene of miR-1a. Statin induced cell apoptosis of skeletal muscle cells, but abolished by downregulating of miR-1a or upregulation of MAP3K1. Further, the effects of miR-1a inhibition on statin-induced cell apoptosis were ablated by MAP3K1 siRNA. In ApoE-/- mice, statin induced cell apoptosis of skeletal muscle cells and decreased exercise capacity in mice infected with vector, but not in mice with lentivirus-mediated miR-1a gene silence.

Conclusion

Statin causes skeletal injury through induction of miR-1a excessive expression to decrease MAP3K1 gene expression.

SUBMITTER: Fu CN

PROVIDER: S-EPMC8109097 | biostudies-literature | 2021 Apr

REPOSITORIES: biostudies-literature

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Publications

Excessive expression of miR-1a by statin causes skeletal injury through targeting mitogen-activated protein kinase kinase kinase 1.

Fu Chang-Ning CN Song Jia-Wen JW Song Zhi-Peng ZP Wang Qian-Wen QW Bai Wen-Wu WW Guo Tao T Li Peng P Liu Chao C Wang Shuang-Xi SX Dong Bo B

Aging 20210416 8

<h4>Backgrounds</h4>A major side effect of statin, a widely used drug to treat hyperlipidemia, is skeletal myopathy through cell apoptosis. The aim of this study is to investigate the roles of microRNA in statin-induced injury.<h4>Methods</h4>Apolipoprotein E knockout (ApoE-/-) mice were administered with simvastatin (20 mg/kg/day) for 8 weeks. Exercise capacity was evaluated by hanging grid test, forelimb grip strength, and running tolerance test.<h4>Results</h4>In cultured skeletal muscle cell ...[more]

PMID: 33864447

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Project description:BackgroundMicroRNAs (miRNAs) play critical roles in regulating virus infection and replication. However, the mechanism by which miRNA regulates Zika virus (ZIKV) replication remains elusive. We aim to explore how the differentially expressed miR-103a-3p regulates ZIKV replication and to clarify the underlying molecular mechanism.MethodsSmall RNA sequencing (RNA-Seq) was performed to identify differentially expressed miRNAs in A549 cells with or without ZIKV infection and some of the dysregulated miRNAs were validated by quantitative real time PCR (qRT-PCR). The effect of miR-103a-3p on ZIKV replication was examined by transfecting miR-103a-3p mimic or negative control (NC) into A549 cells with or without p38 mitogen-activated protein kinase (MAPK) inhibitor SB203580 and expression levels of ZIKV NS5 mRNA and NS1 protein were detected by qRT-PCR and Western blot, respectively. The potential target genes for miR-103a-3p were predicted by four algorithms and further validated by mutation analysis through luciferase reporter assay. The predicated target gene OTU deubiquitinase (DUB) 4 (OTUD4) was over-expressed by plasmid transfection or silenced by siRNA transfection into cells prior to ZIKV infection. Activation status of p38 MAPK signaling pathway was revealed by looking at the phosphorylation levels of p38 (p-p38) and HSP27 (p-HSP27) by Western blot.ResultsThirty-five differentially expressed miRNAs in ZIKV-infected A549 cells were identified by RNA-Seq analysis. Five upregulated and five downregulated miRNAs were further validated by qRT-PCR. One of the validated upregulated miRNAs, miR-103a-3p significantly stimulated ZIKV replication both at mRNA (NS5) and protein (NS1) levels. We found p38 MAPK signaling was activated following ZIKV infection, as demonstrated by the increased expression of the phosphorylation of p38 MAPK and HSP27. Blocking p38 MAPK signaling pathway using SB203580 inhibited ZIKV replication and attenuated the stimulating effect of miR-103a-3p on ZIKV replication. We further identified OTUD4 as a direct target gene of miR-103a-3p. MiR-103a-3p over-expression or OTUD4 silencing activated p38 MAPK signaling and enhanced ZIKV replication. In contrast, OTUD4 over-expression inhibited p38 MAPK activation and decreased ZIKV replication. In addition, OTUD4 over-expression attenuated the stimulating effect of miR-103a-3p on ZIKV replication and activation of p38 MAPK signaling.ConclusionZika virus infection induced the expression of miR-103a-3p, which subsequently activated p38 MAPK signaling pathway by targeting OTUD4 to facilitate ZIKV replication.

Dataset Information

Excessive expression of miR-1a by statin causes skeletal injury through targeting mitogen-activated protein kinase kinase kinase 1.

Backgrounds

Methods

Results

Conclusion

Publications

Excessive expression of miR-1a by statin causes skeletal injury through targeting mitogen-activated protein kinase kinase kinase 1.

Similar Datasets

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