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Possible mechanisms underlying statin-induced skeletal muscle toxicity in L6 fibroblasts and in rats
Mai Itagaki1, Akira Takaguri, Seiichiro Kano
1Division of Pharmacology, Hokkaido Pharmaceutical University School of Pharmacy, Otaru, Japan.
Abstract:
3-Hydroxy-3-methylglutaryl CoA reductase inhibitors (statins) are safe and well-tolerated therapeutic drugs. However, they occasionally induce myotoxicity such as myopathy and rhabdomyolysis. Here, we investigated the mechanism of statin-induced myotoxicity in L6 fibroblasts and in rats in vivo. L6 fibroblasts were differentiated and then treated with pravastatin, simvastatin, or fluvastatin for 72 h. Hydrophobic simvastatin and fluvastatin decreased cell viability in a dose-dependent manner via apoptosis characterized by typical nuclear fragmentation and condensation and caspase-3 activation. Both hydrophobic statins transferred RhoA localization from the cell membrane to the cytosol. These changes induced by both hydrophobic statins were completely abolished by the co-application of geranylgeranylpyrophosphate (GGPP). Y27632, a Rho-kinase inhibitor, mimicked the hydrophobic statin-induced apoptosis. Hydrophilic pravastatin did not affect the viability of the cells. Fluvastatin was continuously infused (2.08 mg/kg at an infusion rate of 0.5 mL/h) into the right internal jugular vein of the rats in vivo for 72 h. Fluvastatin infusion significantly elevated the plasma CPK level and transferred RhoA localization in the skeletal muscle from the cell membrane to the cytosol. In conclusion, RhoA dysfunction due to loss of lipid modification with GGPP is involved in the mechanisms of statin-induced skeletal muscle toxicity.
Insights
Hydrophobic statins can cause muscle toxicity by disrupting RhoA function, leading to apoptosis. Restoring geranylgeranylpyrophosphate (GGPP) levels prevents this statin-induced myopathy.
Area of Science:
- Biochemistry
- Molecular Biology
- Pharmacology
Background:
- 3-Hydroxy-3-methylglutaryl CoA reductase inhibitors (statins) are widely used to lower cholesterol.
- While generally safe, statins can cause myotoxicity, including myopathy and rhabdomyolysis.
- The precise mechanisms underlying statin-induced muscle damage remain incompletely understood.
Purpose of the Study:
- To investigate the molecular mechanisms of statin-induced myotoxicity.
- To explore the role of RhoA signaling in statin-induced muscle cell apoptosis.
- To differentiate the effects of hydrophobic versus hydrophilic statins on muscle cells.
Main Methods:
- L6 myoblast cell cultures were treated with pravastatin, simvastatin, or fluvastatin.
- Cell viability, apoptosis markers (nuclear fragmentation, caspase-3 activation), and RhoA localization were assessed.
- In vivo studies involved continuous intravenous infusion of fluvastatin in rats.
- Plasma creatine phosphokinase (CPK) levels and RhoA localization in skeletal muscle were measured.
Main Results:
- Hydrophobic statins (simvastatin, fluvastatin) induced apoptosis and decreased cell viability in L6 fibroblasts.
- Hydrophobic statins caused a shift in RhoA localization from the cell membrane to the cytosol.
- Co-application of geranylgeranylpyrophosphate (GGPP) abolished these effects.
- A Rho-kinase inhibitor mimicked the apoptotic effects of hydrophobic statins.
- In vivo fluvastatin infusion elevated plasma CPK and altered RhoA localization in rat skeletal muscle.
- Hydrophilic pravastatin did not induce significant toxicity.
Conclusions:
- RhoA dysfunction, specifically the loss of GGPP-dependent lipid modification, is implicated in statin-induced skeletal muscle toxicity.
- Hydrophobic statins appear to mediate toxicity through interference with RhoA prenylation.
- These findings highlight a potential therapeutic target for mitigating statin-induced myopathy.
