Association of miR-145 With Statin-Induced Skeletal Muscle Toxicity in Human Rhabdomyosarcoma RD Cells

J Pharm Sci. 2017 Sep;106(9):2873-2880. doi: 10.1016/j.xphs.2017.04.005. Epub 2017 Apr 21.


Skeletal muscle toxicity including rhabdomyolysis in severe case is a major side effect of low-density lipoprotein cholesterol-lowering statin drugs. We, therefore, aimed at exploring microRNA (miRNA) expression to understand molecular mechanism of statin-induced toxicity. miRNA expression profiling assay for cerivastatin (1 μM for 48 h)-treated RD cells showed more than 2-fold decrease in 26 miRNA expressions with miR-145 being downregulated prominently. When RD cells were treated with cerivastatin at 10 μM for 36 h, mitochondrial dysfunction was observed in 49.6% of the population without causing apoptosis, whereas 82% underwent apoptosis when treated at 10 μM for 48 h. In RD cells treated under the same condition (10 μM for 48 h), miR-145 expression and mRNA expressions of proapoptotic APAF1 and CASP10 genes, potential targets of miR-145, significantly decreased and increased, respectively. Moreover, enforced expression of miR-145 reduced apoptotic cell population of cerivastatin-treated RD cells (10 μM for 36 h). Because miR-145 increased in extracellular medium from cerivastatin-treated RD cells, miR-145 was suggested to be secreted in response to statin-induced toxicity. These results provide a new rationale for statin's toxicity that statin-induced apoptosis is caused by enhanced expression of proapoptotic genes mediated by decreased intracellular miR-145 due to statin-induced mitochondrial dysfunction.

Keywords: apoptosis; biomarker; miR-145; microRNA; skeletal muscle toxicity; statins.

MeSH terms

  • Apoptosis / drug effects
  • Cell Line, Tumor
  • Down-Regulation / drug effects
  • Humans
  • Hydroxymethylglutaryl-CoA Reductase Inhibitors / adverse effects*
  • MicroRNAs / genetics*
  • Mitochondria / drug effects
  • Mitochondria / genetics
  • Mitochondria / metabolism
  • Mitochondria / pathology
  • Muscle, Skeletal / drug effects*
  • Muscle, Skeletal / metabolism
  • Muscle, Skeletal / pathology
  • Pyridines / adverse effects*
  • Transcriptome / drug effects*


  • Hydroxymethylglutaryl-CoA Reductase Inhibitors
  • MIRN145 microRNA, human
  • MicroRNAs
  • Pyridines
  • cerivastatin