Statins, taken by more than 200 million people worldwide, lower cholesterol and help prevent heart attacks and strokes. However, muscle pain, weakness and fatigue can prompt some patients to discontinue treatment, potentially sacrificing important cardiovascular protection. Although severe muscle breakdown affects only a small proportion of patients, it can lead to kidney failure. Researchers at the University of British Columbia, working with colleagues at the University of Wisconsin-Madison, have now identified a molecular mechanism that helps explain these complications.
The team used cryo-electron microscopy to examine how atorvastatin, a widely prescribed statin, interacts with the ryanodine receptor, RyR1. This protein regulates calcium release within muscle cells, normally opening when muscles need to contract. The researchers discovered that three statin molecules occupy a particular pocket in the protein. One initially binds to the closed channel, increasing its likelihood of opening; two additional molecules then enter the pocket and stabilise the open state. The resulting continuous calcium leak can injure muscle tissue. Although the investigation focused on atorvastatin, the findings suggest that other statins could interact with the channel in a similar way.
Published in Nature Communications, the findings could guide efforts to modify the molecular features responsible for these unwanted interactions without compromising cholesterol reduction. Such changes might eventually produce better-tolerated medicines, helping patients maintain treatment with fewer muscle-related complications. Further research and drug development will be necessary before this structural understanding translates into new therapies.
