Scientists at the University of British Columbia (UBC), working with researchers at the University of Wisconsin-Madison, have identified a molecular mechanism that may explain these statin-related muscle complications. Published in Nature Communications, the findings could support the development of safer statins that maintain their cholesterol-lowering benefits while minimizing muscle damage.

How statins may cause harmful calcium leakage

To investigate what happens inside muscle cells, the researchers used cryo-electron microscopy, an advanced imaging technique that allows scientists to examine protein structures in remarkable detail. Their research focused on the ryanodine receptor, or RyR1, a protein that regulates calcium movement within muscle cells.

Under normal conditions, RyR1 acts as a controlled gateway, releasing calcium when muscles need to contract. The researchers found that statins can interfere with this process by keeping the channels open. As a result, calcium continually leaks into areas that must be carefully regulated, creating conditions that can damage muscle tissue.

“We were able to see almost atom by atom how statins latch into this channel,” said lead author Dr. Stephen Molinaroro, a postdoctoral researcher in UBC’s Department of Biochemistry and Molecular Biology. “This calcium leak explains why some patients experience muscle pain and, in extreme cases, life-threatening complications.”

Three statin molecules reveal a mechanism behind muscle damage

The researchers focused on atorvastatin, a commonly prescribed cholesterol-lowering drug. Although atorvastatin was the main focus of the study, the findings suggest that similar interactions may occur with other drugs in the statin class.

One of the most striking discoveries was the unusual way statin molecules attach to calcium channels. Rather than acting individually, three molecules occupy specific pockets within the protein. The first binds while the channel is closed, increasing the likelihood that the channel will open. Two additional molecules then enter the pocket and keep the channel open, allowing calcium to continue leaking.

“This is the first time that we have a clear picture of how statins activate this channel,” said senior author Dr. Philip van Petegem, a professor at UBC’s Institute of Life Sciences. “This is a major step forward because it provides a roadmap for designing statins that do not interact with muscle tissue.”

This detailed understanding could help drug developers address the molecular cause of statin-related muscle problems. By changing the features of statin molecules that interfere with muscle proteins, scientists may be able to reduce unwanted effects without compromising the drugs’ ability to control cholesterol.

A potential path to safer cholesterol treatments

More than 200 million people worldwide use statins. Although severe muscle damage occurs in only a small percentage of patients, less severe symptoms—including pain, weakness and fatigue—are widespread. These symptoms can be so disruptive that some people stop taking their medication, potentially losing important protection against cardiovascular disease.

The discovery could ultimately help researchers develop better-tolerated cholesterol treatments, allowing more patients to continue taking medicines that reduce their risk of heart attack and stroke.

Achieving this level of understanding required highly detailed imaging. Working with UBC Faculty of Medicine’s High-Resolution Macromolecule Cryo-Electron Microscopy Facility, the research team observed precisely how statin molecules interact with muscle proteins. These structural insights connect long-standing drug safety concerns to specific molecular processes and provide valuable information for future drug development.

“Statins have been a cornerstone of cardiovascular treatment for decades,” said Dr. van Petegem. “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 required before these findings can be translated into new treatments. However, they represent a promising direction for the millions of people who rely on statins to protect their hearts. Future drugs with fewer muscle-related complications could make treatment more comfortable and improve patients’ quality of life.