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. Two additional molecules then enter the pocket and hold the channel open, allowing calcium to continue leaking.
“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.”
This detailed understanding could give drug developers a way to address the problem at its source. By modifying the specific 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 Toward Safer Cholesterol Drugs
More than 200 million people worldwide use statins. Although severe muscle injury occurs in only a small percentage of patients, less serious problems such as soreness, weakness, and fatigue are considerably more widespread. These symptoms can be disruptive enough that some people discontinue their medication, potentially losing important protection against cardiovascular disease.
The 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 imaging. Working with the high-resolution macromolecular cryo-electron microscopy facility at UBC’s faculty of medicine, the team was able to observe precisely how statin molecules interact with the muscle protein. These structural insights connect a longstanding drug safety concern to a specific molecular process, providing valuable information for future medication development.
“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.”
Although additional research and drug development will be needed before these findings translate into new treatments, they offer a promising direction. For millions of people who depend on statins to protect their hearts, future medications with fewer muscle-related complications could make treatment more comfortable and improve everyday quality of life.
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