Statins are very important in lowering cholesterol. However these cause some people to develop muscle pain or weakness, while a small number experience serious muscle breakdown that can potentially cause kidney failure.
Finally the 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.
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."
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.
Hopefully, 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.
Finally the 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.
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."
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.
Hopefully, 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.
