Statins, taken by more than 200 million people worldwide, lower cholesterol and help prevent heart attacks and strokes. Their benefits, however, can be accompanied by muscle pain, weakness, and fatigue. Severe muscle breakdown, which affects a small proportion of patients, can potentially lead to kidney failure. Even less serious symptoms may prompt patients to discontinue treatment, potentially sacrificing important cardiovascular protection.
A research team from the University of British Columbia and the University of Wisconsin-Madison has pinpointed a molecular process that may account for these complications. In their Nature Communications paper, cryo-electron microscopy revealed how statins interact with the ryanodine receptor, RyR1. This protein regulates calcium release within muscle cells, normally opening when muscles need to contract. Focusing on the widely prescribed drug atorvastatin, the team found that three statin molecules occupy a particular pocket in the protein. The first binds to the closed channel and increases its likelihood of opening; two additional molecules then enter the pocket and hold the channel open. The resulting continuous calcium leak can injure muscle tissue. Although atorvastatin was the principal focus, the findings suggest that other statins could interact with the channel similarly.
The structural findings offer a potential route toward medications that retain their cholesterol-lowering effects while causing fewer muscle complications. By modifying the molecular features responsible for interactions with muscle proteins, drug developers may be able to address the damage at its origin. Further research and development will be necessary before this approach produces new treatments, but the discovery provides a specific molecular target for efforts to improve statin safety.
