Statins are among the most important medications for preventing cardiovascular disease. By lowering cholesterol, they have helped save millions of lives and reduce the likelihood of heart attacks and strokes. However, these benefits can come with unwanted effects.
Some patients develop muscle pain or weakness, while a small number experience serious muscle breakdown that can potentially cause kidney failure. Scientists at the University of British Columbia (UBC), working with colleagues at the University of Wisconsin-Madison, have identified a molecular mechanism that helps explain these complications. Their findings, published in Nature Communications, could guide the development of safer statins that maintain their cholesterol-lowering benefits while minimizing muscle damage.
How Statins Trigger a Harmful Calcium Leak To investigate what happens inside muscle cells, the researchers used cryo-electron microscopy, an advanced imaging method that allows scientists to examine protein structures in remarkable detail. Their investigation centered on the ryanodine receptor (RyR1), a protein that regulates the movement of calcium within muscle cells. Under normal conditions, this protein functions as a controlled gateway, releasing calcium when muscles need to contract.
The researchers found that statins can interfere with this process by holding the channel open. As a result, calcium escapes continuously into areas where it should be carefully regulated, creating conditions that can injure muscle tissue. "We were able to see, almost atom by atom, how statins latch onto this channel," said lead author Dr.
Steven Molinarolo, a postdoctoral researcher in UBC's department of biochemistry and molecular biology. "That leak of calcium explains why some patients experience muscle pain or, in extreme cases, life-threatening complications." Three Statin Molecules Reveal the Mechanism Behind Muscle Damage The researchers concentrated on atorvastatin, a commonly prescribed medication for lowering cholesterol. Although this particular drug was the main focus, their results suggest that similar interactions could occur with other medications in the statin family.
One of the most striking discoveries was the unusual way statin molecules attach to the calcium channel. Rather than acting individually, three molecules occupy a specific pocket within the protein. The first binds while the channel is closed, making it more likely to open.
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