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

• Published in: Biochimica et biophysica acta Vol. 1840; no. 1; pp. 406 - 415
• Main Authors: Simsek Ozek, Nihal, Bal, I. Burak, Sara, Yildirim, Onur, Rustu, Severcan, Feride
• Format: Journal Article
• Language: English
• Published: Netherlands Elsevier B.V 01-01-2014
• Subjects: Animals; Contractility; Diaphragm; Extensor digitorum longus; Fourier Transform Infrared spectroscopy; Hydroxymethylglutaryl-CoA Reductase Inhibitors - toxicity; Ion Channels - chemistry; Ion Channels - metabolism; Male; Muscle Contraction - drug effects; Muscle Fibers, Fast-Twitch - drug effects; Muscle Fibers, Fast-Twitch - pathology; Muscle Fibers, Slow-Twitch - drug effects; Muscle Fibers, Slow-Twitch - pathology; Muscle, Skeletal - drug effects; Muscle, Skeletal - pathology; Muscular Diseases - chemically induced; Muscular Diseases - pathology; Rats; Rats, Wistar; Simvastatin - toxicity; Soleus; Spectroscopy, Fourier Transform Infrared; Statin; SOL; Extensor digitorum longus; Soleus; ATR-FTIR; FTIR; Contractility; Statin; Diaphragm; EDL; DIA; Fourier Transform Infrared spectroscopy; attenuated total reflectance Fourier transform infrared spectroscopy
• ISSN: 0304-4165; 0006-3002; 1872-8006
• DOI: 10.1016/j.bbagen.2013.09.010

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.
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.
With simvastatin administration (30days, 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 β-sheet and an increase in random coil, aggregated and antiparallel β-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.
Simvastatin-induced structural and functional alterations are more profound in the fast-twitch than in the slow-twitch muscles.
Myotoxic effects of simvastatin are primarily observed in the fast-twitch muscles.
•Simvastatin treatments caused a depression of force production in muscles.•Simvastatin treatment reduced the macromolecular content and function of muscles.•Myotoxic effects of simvastatin predominantly occurred in EDL muscles.•FTIR spectroscopy is an efficient tool to examine drug-induced toxicity in tissues.