Statins are among the most important medications for preventing cardiovascular disease. By lowering cholesterol levels, they have helped save millions of lives and reduce the risk of heart attacks and strokes. However, these benefits can have undesirable effects. Some patients develop muscle pain or weakness, while a small number experience severe 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 Natural communicationscould guide the development of safer statins that maintain their cholesterol-lowering benefits while minimizing muscle damage.
How Statins Trigger Harmful Calcium Leak
To study what’s happening inside muscle cells, researchers used cryo-electron microscopy, an advanced imaging method that allows scientists to examine protein structures in remarkable detail. Their investigation focused on the ryanodine receptor (RyR1), a protein that regulates the movement of calcium into muscle cells.
Under normal conditions, this protein functions as a controlled gateway, releasing calcium when muscles need to contract. Researchers have found that statins can interfere with this process by keeping the channel open. As a result, calcium continually leaks into areas where it needs to be carefully regulated, creating conditions that can damage muscle tissue.
“We were able to see, almost atom by atom, how statins bind to this channel,” said lead author Dr. Steven Molinarolo, a postdoctoral researcher in the department of biochemistry and molecular biology at UBC. “This calcium leak 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 focused on atorvastatin, a drug commonly prescribed to lower cholesterol. Although this particular drug has been the center of attention, their results suggest that similar interactions could occur with other drugs in the statin family.
One of the most striking findings was the unusual way in which statin molecules bind to the calcium channel. Rather than acting individually, three molecules occupy a specific pocket within the protein. The first binds when the channel is closed, making it more likely to open. Two additional molecules then enter the pocket and keep the channel open, allowing calcium to continue to escape.
“This is the first time we have a clear picture of how statins activate this channel,” said Dr. Filip Van Petegem, lead author and professor in the UBC Institute of Life Sciences. “This is a big step forward because it gives us a roadmap for designing statins that do not interact with muscle tissue.”
This detailed understanding could give drug developers a way to address the problem at its source. By modifying the specific characteristics of statin molecules that interfere with muscle proteins, scientists may be able to reduce adverse effects without compromising the drugs’ ability to control cholesterol.
A potential path to safer cholesterol drugs
More than 200 million people worldwide use statins. Although serious muscle damage only occurs in a small percentage of patients, less serious problems such as pain, weakness, and fatigue are considerably more prevalent. These symptoms can be disruptive enough that some people stop taking their medications, losing important protection against cardiovascular disease.
This discovery could eventually help researchers create treatments that are easier to tolerate, allowing more patients to continue taking medications that reduce their risk of heart attacks and strokes.
Achieving this level of understanding required exceptionally detailed imagery. Working with the high-resolution macromolecular cryoelectron microscopy facility at UBC’s Faculty of Medicine, the team was able to observe precisely how statin molecules interact with muscle proteins. This structural knowledge links a long-standing concern in drug safety to a specific molecular process, providing valuable information for future drug development.
“Statins have been a cornerstone of cardiovascular care for decades,” said Dr. Van Petegem. “Our goal is to make them even safer, so that patients can benefit from them without fear of serious side effects.”
Although additional research and drug development are needed before these findings translate into new treatments, they offer a promising direction. For millions of people who rely on statins to protect their hearts, future drugs with fewer muscle complications could make treatment more comfortable and improve daily quality of life.
Gn Health
