Excessive expression of miR-1a by statin causes skeletal injury through targeting mitogen-activated protein kinase kinase kinase 1.
Aging (Albany NY)
; 13(8): 11470-11490, 2021 04 16.
Article
em En
| MEDLINE
| ID: mdl-33864447
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.Palavras-chave
Texto completo:
1
Base de dados:
MEDLINE
Assunto principal:
Fibras Musculares Esqueléticas
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Inibidores de Hidroximetilglutaril-CoA Redutases
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MicroRNAs
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MAP Quinase Quinase Quinase 1
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Doenças Musculares
Tipo de estudo:
Diagnostic_studies
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Etiology_studies
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Prognostic_studies
Limite:
Animals
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Humans
Idioma:
En
Revista:
Aging (Albany NY)
Assunto da revista:
GERIATRIA
Ano de publicação:
2021
Tipo de documento:
Article