Excessive expression of miR-1a by statin causes skeletal injury through targeting mitogen-activated protein kinase kinase kinase 1
| Autor: | Bo Dong, Wen-Wu Bai, Jia-Wen Song, Chang-Ning Fu, Chao Liu, Peng Li, Shuang-Xi Wang, Zhi-Peng Song, Qian-Wen Wang, Tao Guo |
|---|---|
| Rok vydání: | 2021 |
| Předmět: |
Simvastatin
Aging Statin Mice Knockout ApoE medicine.drug_class Muscle Fibers Skeletal Primary Cell Culture MAP Kinase Kinase Kinase 1 Hyperlipidemias MAP3K1 Mitogen-activated protein kinase kinase Pharmacology Mice Muscular Diseases Physical Conditioning Animal Animals Humans Medicine RNA Small Interfering Protein kinase A Cells Cultured business.industry Kinase statin apoptosis mitogen-activated protein kinase kinase kinase 1 Skeletal muscle Cell Biology microRNA-1a Up-Regulation Disease Models Animal MicroRNAs medicine.anatomical_structure Apoptosis lipids (amino acids peptides and proteins) Hydroxymethylglutaryl-CoA Reductase Inhibitors business Research Paper myopathy medicine.drug |
| Zdroj: | Aging (Albany NY) |
| ISSN: | 1945-4589 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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