Simvastatin activates single skeletal RyR1 channels but exerts more complex regulation of the cardiac RyR2 isoform.
Venturi E., Lindsay C., Lotteau S., Yang Z., Steer E., Witschas K., Wilson AD., Wickens JR., Russell AJ., Steele D., Calaghan S., Sitsapesan R.
Statins are amongst the most widely prescribed drugs for those at risk of cardiovascular disease, lowering cholesterol levels by inhibiting 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase. Although effective in prevention of cardiovascular disease, statin use is associated with muscle weakness, myopathies and, in rare cases, fatal rhabdomyolysis. As simvastatin, a commonly prescribed statin, can promote Ca2+ release from sarcoplasmic reticulum (SR) vesicles, we investigated if simvastatin could directly activate skeletal (RyR1) and cardiac (RyR2) ryanodine receptors.RyR1 and RyR2 single-channel behaviour was investigated after incorporation of sheep cardiac or mouse skeletal SR into planar phospholipid bilayers under voltage-clamp conditions. LC-MS was used to monitor the kinetics of interconversion of simvastatin between hydroxy-acid and lactone forms during these experiments. Cardiac and skeletal myocytes were permeabilised to examine simvastatin modulation of SR Ca2+ release.Hydroxy acid simvastatin (active at HMG-CoA reductase) significantly and reversibly increased RyR1 open probability (Po) and shifted the distribution of Ca2+ spark frequency towards higher values in skeletal fibres. In contrast, simvastatin reduced RyR2 Po and shifted the distribution of spark frequency towards lower values in ventricular cardiomyocytes. The lactone pro-drug form of simvastatin (inactive at HMG-CoA reductase) was also an effective activator of RyR1, suggesting that the HMG-CoA inhibitor pharmacophore was not responsible for RyR1 activation.Our results indicate that simvastatin interacts with RyR1 to increase SR Ca2+ release and thus may contribute to its reported adverse effects on skeletal muscle. The ability of low concentrations of simvastatin to reduce RyR2 Po may also protect against Ca2+ -dependent arrhythmias and sudden cardiac death.