What the study found
A team from the University of British Columbia, together with collaborators at the University of Wisconsin-Madison, has pinpointed a molecular process that may account for muscle problems in some people who take statins. According to Science Daily, which published material supplied by UBC, the results appear in Nature Communications.
Statins are prescribed to lower cholesterol and cut the risk of heart attacks and strokes. Some patients, however, develop muscle pain or weakness. A small number suffer severe muscle breakdown, which can lead to kidney failure.
To see what the drug does inside muscle tissue, the researchers used cryo-electron microscopy, a technique that reveals the detailed shapes of proteins. They examined the ryanodine receptor, known as RyR1, which controls how calcium moves within muscle cells.
A channel stuck open
In healthy muscle, RyR1 works like a gate. It lets calcium out when a muscle needs to contract and otherwise stays shut. The team reported that statins disrupt this arrangement by propping the gate open, so calcium keeps seeping out in places where its movement is normally tightly managed. That steady leak can harm 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. He added that the calcium leak "explains why some patients experience muscle pain or, in extreme cases, life-threatening complications."
Three molecules in one pocket
The experiments centered on atorvastatin, a commonly prescribed cholesterol medicine. The authors say their results suggest other drugs in the statin class could interact with the channel in comparable ways, though the study itself concentrated on this one.
The researchers found that the drug does not act one molecule at a time. Three statin molecules fit into a single pocket of the protein. The first attaches while the channel is closed, which makes opening more likely. Two more then join and keep the channel open, so calcium continues to escape.
"This is the first time we've had a clear picture of how statins activate this channel," said Dr. Filip Van Petegem, the senior author and a professor at UBC's Life Sciences Institute. He called it "a big step forward because it gives us a roadmap for designing statins that don't interact with muscle tissue."
Why tolerability matters
More than 200 million people around the world take statins, according to the source. Severe muscle injury affects only a small share of them, but milder complaints such as soreness, weakness and fatigue are much more common. For some patients these symptoms are troublesome enough that they stop treatment, which can leave them without protection against cardiovascular disease.
The researchers say that knowing which parts of a statin molecule interact with the muscle protein could let drug developers alter those features. The aim would be to reduce muscle effects while preserving the ability to lower cholesterol.
What happens next
The imaging was carried out at the high-resolution cryo-electron microscopy facility in UBC's faculty of medicine. The authors say the structural detail ties a long-recognized safety concern to a specific process at the molecular level.
The work is early-stage. Science Daily noted that additional research and drug development will be needed before the findings could become new treatments. Van Petegem said the goal is "to make them even safer, so patients can benefit without fear of serious side effects."
