Structural and functional characterization of simvastatin-induced myotoxicity in different skeletal muscles.

ABSTRACT

BACKGROUND: Statins are the most commonly used drugs for the treatment of hypercholesterolemia. Their most frequent side effect is myotoxicity. To date, it remains unclear whether statins preferentially induce myotoxicity in fast- or in slow-twitch muscles. Therefore, we investigated these effects on fast- (extensor digitorum longus; EDL), slow- (soleus; SOL), and mixed-twitch muscles (diaphragm; DIA) in rats by comparing their contractile and molecular structural properties. METHODS: Simvastatin-induced functional changes were determined by muscle contraction measurements, and drug-induced molecular changes were investigated using Fourier transform infrared (FTIR) and attenuated total reflectance (ATR) FTIR spectroscopy. RESULTS: With simvastatin administration (30 days, 50mg/kg), a depression in the force-frequency curves in all muscles was observed, indicating the impairment of muscle contractility; however, the EDL and DIA muscles were affected more severely than the SOL muscle. Spectroscopic findings also showed a decrease in protein, glycogen, nucleic acid, lipid content and an increase in lipid order and lipid dynamics in the simvastatin-treated muscles. The lipid order and dynamics directly affect membrane thickness. Therefore, the kinetics and functions of membrane ion channels were also affected, contributing to the statin-induced impairment of muscle contractility. Furthermore, a reduction in α-helix and ß-sheet and an increase in random coil, aggregated and antiparallel ß-sheet were observed, indicating the protein denaturation. Spectral studies showed that the extent of molecular structural alterations in the muscles following simvastatin administration was in the order EDL>DIA>SOL. CONCLUSIONS: Simvastatin-induced structural and functional alterations are more profound in the fast-twitch than in the slow-twitch muscles. GENERAL SIGNIFICANCE: Myotoxic effects of simvastatin are primarily observed in the fast-twitch muscles.