Statin activation of skeletal ryanodine receptors (RyR1) is a class effect but separable from HMG‐CoA reductase inhibition

BACKGROUND AND PURPOSE: Statins, inhibitors of HMG‐CoA reductase, are mainstay treatment for hypercholesterolaemia. However, muscle pain and weakness prevent many patients from benefiting from their cardioprotective effects. We previously demonstrated that simvastatin activates skeletal ryanodine receptors (RyR1), an effect that could be important in initiating myopathy. Using a range of structurally diverse statin analogues, we examined structural features associated with RyR1 activation, aiming to identify statins lacking this property. EXPERIMENTAL APPROACH: Compounds were screened for RyR1 activity utilising [(3)H]ryanodine binding. Mechanistic insight into RyR1 activity was studied by incorporating RyR1 channels from sheep, mouse or rabbit skeletal muscle into bilayers. KEY RESULTS: All UK‐prescribed statins activated RyR1 at nanomolar concentrations. Cerivastatin, withdrawn from the market due to life‐threatening muscle‐related side effects, was more effective than currently‐prescribed statins and possessed the unique ability to open RyR1 channels independently of cytosolic Ca(2+). We synthesised the one essential structural moiety that all statins must possess for HMG‐CoA reductase inhibition, the R‐3,5‐dihydroxypentanoic acid unit, and it did not activate RyR1. We also identified five analogues retaining potent HMG‐CoA reductase inhibition that inhibited RyR1 and four that lacked the ability to modulate RyR1. CONCLUSION AND IMPLICATIONS: That cerivastatin activates RyR1 most strongly supports the hypothesis that RyR1 activation is implicated in statin‐induced myopathy. Demonstrating that statin regulation of RyR1 and HMG‐CoA reductase are separable effects will allow the role of RyR1 in statin‐induced myopathy to be further elucidated by the tool compounds we have identified, allowing development of effective cardioprotective statins with improved patient tolerance.