Cryo-electron microscopy shows how statins open a muscle calcium channel

A drug with a known side effect

Statins lower cholesterol and are among the most important medications for preventing cardiovascular disease, reducing the likelihood of heart attacks and strokes. Their benefits can come with unwanted effects: some patients develop muscle pain or weakness, and a small number experience serious muscle breakdown that can potentially cause kidney failure. Scientists at the University of British Columbia, working with colleagues at the University of Wisconsin-Madison, have identified a molecular mechanism that helps explain these complications. The findings were published in Nature Communications.

Calcium that will not stop leaking

To see what happens inside muscle cells, the researchers used cryo-electron microscopy, an imaging method that allows scientists to examine protein structures in remarkable detail. Their investigation centred on the ryanodine receptor (RyR1), a protein that regulates the movement of calcium within muscle cells. Under normal conditions it functions as a controlled gateway, releasing calcium when muscles need to contract.

The team found that statins can interfere with this process by holding the channel open. Calcium then 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 molecules, one pocket

The researchers concentrated on atorvastatin, a commonly prescribed medication for lowering cholesterol, although their results suggest that similar interactions could occur with other medications in the statin family. Rather than acting individually, three statin molecules occupy a specific pocket within the protein. The first binds while the channel is closed, making it more likely to open; two additional molecules then enter the pocket and hold the channel open, allowing calcium to continue leaking.

The Nature Communications paper describes the same sequence in structural terms. One statin per subunit can bind to the transmembrane region of a closed RyR1, with small structural perturbations that prime the channel for opening. Binding of two additional statins per subunit is associated with a widening of the pseudo-voltage sensing domain, which triggers opening of the pore. The paper firmly establishes RyR1 as an unintended off-target for atorvastatin, and notes that sequence variants in RyR1 correlate with intolerance to statins.

"This is the first time we've had a clear picture of how statins activate this channel," said Dr. Filip Van Petegem, senior author and professor at UBC's Life Sciences Institute. "It's a big step forward because it gives us a roadmap for designing statins that don't interact with muscle tissue."

How often muscles are affected

More than 200 million people worldwide use statins. Severe muscle symptoms arise in 0.1% to 0.5% of statin users, according to the Nature Communications paper, while observational studies suggest that general muscle pain may be reported by as many as 10% to 25% of patients. The paper notes that the higher figure is heavily debated. Less serious problems such as soreness, weakness and fatigue are considerably more widespread than severe injury, and can be disruptive enough that some people discontinue their medication, potentially losing important protection against cardiovascular disease.

The paper lists risk factors for muscle side effects, including other drugs that affect the metabolism of statins by inhibiting cytochrome P450, increased physical activity, advanced age, physical frailty and alcohol use. It also records that cerivastatin, approved by the FDA in 1997, was withdrawn from the market four years later after 52 deaths as a result of severe rhabdomyolysis. Myotoxicity is readily observed through increased creatine kinase in the blood, and the issues are usually resolved after stopping statin treatment.

What could change, and what is unresolved

Comparing atorvastatin's binding to HMG-CoA reductase, its intended target, with its binding to RyR1 offers clues about how to modify the statin so that it binds the receptor less, while leaving binding to HMG-CoA reductase unperturbed. "Statins have been a cornerstone of cardiovascular care for decades," Van Petegem said. "Our goal is to make them even safer, so patients can benefit without fear of serious side effects." Additional research and drug development will be needed before these findings translate into new treatments.

The two sources do not agree on dating: the ScienceDaily release is dated October 20, 2026, while the identifier of the Nature Communications article indicates 2025.