Simvastatin activates single skeletal RyR1 channels but exerts more complex regulation of the cardiac RyR2 isoform

Abstract

Background and PurposeStatins are amongst the most widely prescribed drugs for those at risk of cardiovascular disease, lowering cholesterol levels by inhibiting 3‐hydroxy‐3‐methylglutaryl (HMG)‐CoA reductase. Although effective at preventing cardiovascular disease, statin use is associated with muscle weakness, myopathies and, occasionally, fatal rhabdomyolysis. As simvastatin, a commonly prescribed statin, promotes Ca2+ release from sarcoplasmic reticulum (SR) vesicles, we investigated if simvastatin directly activates skeletal (RyR1) and cardiac (RyR2) ryanodine receptors.Experimental ApproachRyR1 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.Key ResultsHydroxy 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) also activated RyR1, suggesting that the HMG‐CoA inhibitor pharmacophore was not responsible for RyR1 activation.Conclusion and ImplicationsSimvastatin 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.

A Mechanism for Statin-Induced Susceptibility to Myopathy

“…In planar lipid bilayers, simvastatin increases the open probability of RyR1 but not RyR2 (28). Similarly, acute application of simvastatin to permeabilized cells shifts the distribution of Ca 2+ spark frequency toward higher values in skeletal fibers (which express predominantly RyR1) but lower values in cardiac myocytes (which express RyR2) (28). Thus, a central role for RyR in statin myopathy fully explains the selectivity of this effect for skeletal over cardiac muscle.…”

“…In addition, direct effects of the statin molecule on RyR might also contribute to selective skeletal myopathy. In planar lipid bilayers, simvastatin increases the open probability of RyR1 but not RyR2 (28). Similarly, acute application of simvastatin to permeabilized cells shifts the distribution of Ca 2+ spark frequency toward higher values in skeletal fibers (which express predominantly RyR1) but lower values in cardiac myocytes (which express RyR2) (28).…”

“…FDB is predominantly type IIa; the choice of this muscle was informed by the short length of the fibers that allows the isolation and study of intact cells. In some cases, fibers were permeabilized by 2-min exposure to 0.005% (w/v) saponin (28). Rat cardiac myocytes were isolated from Langendorff-perfused hearts by collagenase and protease digestion (29).…”

The protective effect of simvastatin against ultraviolet B-induced corneal endothelial cell death

“…Simvastatin is a widely used specific inhibitor of 3-hydroxy-3-methyl-glutaryl-CoA reductase and can reduce the level of low-density lipoprotein cholesterol as well as exert anti-inflammatory effects. [ 20 21 ] A previous clinical study has demonstrated that simvastatin may be associated with visual field stabilization in patients with normal tension glaucoma. A larger scale randomized controlled trial and cost-effective analyses seem to be approved.…”

Impact of statin intake on malignant hyperthermia: an in vitro and in vivo swine study

“…Physiological studies of the isolated ryanodine receptor RyR1 in lipid bilayers recently characterized an interaction with simvastatin which suggested that this drug may facilitate calcium ion leakage [11], a known feature of MHS muscle. Acute exposure to statins in vitro elicits contractures in muscle from MH-susceptible (MHS) pigs but not in muscle from non-susceptible (MHN) animals [12].…”