A new study explains how cholesterol-lowering medications can lead to muscle damage and identifies a possible approach to making these treatments safer.
Statins have dramatically improved cardiovascular health by lowering cholesterol levels and reducing the likelihood of heart attacks and strokes. Yet many people who take these medications experience unwanted muscle symptoms, including soreness, weakness, and in rare situations, severe muscle breakdown that can harm the kidneys.
Identifying the molecular cause of statin-related muscle damage
Researchers at the University of British Columbia, working with colleagues at the University of Wisconsin-Madison, have now uncovered the biological reason behind these side effects. Their results, published last week in Nature Communications, may help guide the development of statins that do not trigger muscle problems.
Using cryo-electron microscopy, a technique capable of visualizing proteins at extremely high resolution, the team observed how statins interact with a key muscle protein known as the ryanodine receptor (RyR1). This receptor controls the flow of calcium inside muscle cells and opens only when a muscle is meant to contract. When statins attach to it, however, the channel is forced open, causing calcium to escape continuously, which can injure the surrounding muscle fibers.
“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.”
How statins bind to the calcium channel
The study examined atorvastatin, one of the most commonly used statins, but the evidence suggests the same effect could occur with other drugs in this class. The researchers found that three statin molecules gather within a single pocket of the protein. The first molecule connects when the channel is closed, preparing it to open, while the other two settle in afterward and push the channel fully open.
“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.”
By adjusting only those parts of the statin molecule that are responsible for the negative effects, scientists could preserve the part that lowers cholesterol while reducing the risk.
Implications for patient safety and future drug design
While severe muscle damage affects only a small fraction of over 200 million statin users worldwide, milder symptoms like aches and fatigue are far more common, and often lead patients to stop treatment. The new findings could help prevent those problems and improve adherence to life-saving therapy.
The research underscores the importance of advanced imaging technology in driving medical breakthroughs. Using the UBC faculty of medicine’s high-resolution macromolecular cryo-electron microscopy facility, the team was able to visualize the statin-protein interaction in extraordinary detail—turning a fundamental question about drug safety into practical insights that could shape the next generation of therapies.
“Statins have been a cornerstone of cardiovascular care for decades,” Dr. Van Petegem said. “Our goal is to make them even safer, so patients can benefit without fear of serious side effects.”
For millions of people who rely on statins, that could mean fewer muscle problems—and a better quality of life.
Reference: “Cryo-electron microscopy reveals sequential binding and activation of Ryanodine Receptors by statin triplets” by Steven Molinarolo, Carmen R. Valdivia, Héctor H. Valdivia and Filip Van Petegem, 20 November 2025, Nature Communications.
DOI: 10.1038/s41467-025-66522-0
Funding: National Institutes of Health
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