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Simvastatin represses protein synthesis in the muscle-derived C₂C₁₂ cell line with a concomitant reduction in

Alexander P Tuckow1, Sarah J Jefferson, Scot R Kimball

  • 1Dept. of Cellular & Molecular Physiology, The Pennsylvania State University College of Medicine, 500 University Drive, Hershey, PA 17033, USA.

American Journal of Physiology. Endocrinology and Metabolism
|January 13, 2011
PubMed

Insights

Statins reduce muscle protein synthesis by decreasing eukaryotic initiation factor 2B (eIF2B) expression and activity. This effect, linked to statin-induced myotoxicity, was reversed by mevalonate.

Area of Science:

  • Biochemistry
  • Molecular Biology
  • Pharmacology

Background:

  • Statins, widely used cholesterol-lowering drugs, are associated with muscle-related side effects (myotoxicity).
  • Mechanisms of statin-induced myotoxicity involve disruptions in muscle protein synthesis and degradation pathways.

Purpose of the Study:

  • To investigate the molecular mechanisms underlying statin-induced reduction in protein synthesis in muscle cells.
  • To explore the role of eukaryotic initiation factor 2B (eIF2B) in simvastatin-induced myotoxicity.

Main Methods:

  • C₂C₁₂ muscle cells were treated with simvastatin (10 microM) or vehicle.
  • Protein synthesis rates were measured using [(35)S]methionine and [(35)S]cysteine incorporation.
  • Expression and activity of eIF2B, and phosphorylation of its ε-subunit, were assessed.
  • Proteasome sensitivity was evaluated.

Main Results:

  • Simvastatin treatment significantly reduced protein synthesis rates in C₂C₁₂ cells.
  • A decrease in both the expression and activity of eukaryotic initiation factor 2B (eIF2B) was observed.
  • Mevalonate co-incubation prevented the simvastatin-induced reductions in protein synthesis and eIF2B levels.
  • Simvastatin induced a proteasome-sensitive decrease in eIF2B protein expression and increased phosphorylation of the eIF2B ε-subunit.

Conclusions:

  • Repression of eIF2B expression and activity is a key mechanism contributing to statin-induced reduction in muscle protein synthesis.
  • These findings provide insights into the molecular basis of statin-induced myotoxicity.
  • Targeting eIF2B regulation may offer strategies to mitigate statin-associated muscle problems.

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