1. Excessive expression of miR-1a by statin causes skeletal injury through targeting mitogen-activated protein kinase kinase kinase 1
- Author
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Bo Dong, Wen-Wu Bai, Jia-Wen Song, Chang-Ning Fu, Chao Liu, Peng Li, Shuang-Xi Wang, Zhi-Peng Song, Qian-Wen Wang, and Tao Guo
- Subjects
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 - 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.
- Published
- 2021