Statins have been transformative for many individuals, by lowering cholesterol and reducing the risk of heart problems and stroke. But statins can also cause muscle weakness and pain and in some cases, can lead to the breakdown of muscle and ultimately, kidney failure. But scientists have now learned why this can happen, which may help researchers develop better statin drugs that don’t have a harmful impact on muscles. The work has been reported in Nature Communications.
In this work, the researchers focused on a common statin known as atorvastatin, but the investigators suggested that the findings may apply to all current statin medications.
The team applied cryo-electron microscopy to show that statins can attach to an important protein in muscle cells known as the ryanodine receptor (RyR1). This protein helps control calcium levels in muscle cells, and allows calcium into cells only when muscles have to contract. But when statins bind to RyR1, this control mechanism fails; calcium continuously enters the cell and may eventually cause damage to muscles.
"We were able to see, almost atom by atom, how statins latch onto this channel," said lead study author Dr. Steven Molinarolo, a postdoctoral researcher at the University of British Columbia (UBC). "That leak of calcium explains why some patients experience muscle pain or in extreme cases, life-threatening complications."
When statins attach to RyR1, three molecules gather in a pocket of the protein; the first binds to an open channel. Then two more molecules bind too, which forces the channel open.
Although serious muscle problems only affect a small proportion of statin users, there are minor side effects that are felt by far more statin users, such as aches. Now researchers may be bale to design better statins that don’t cause these problems.
"Statins have been a cornerstone of cardiovascular care for decades," said senior study author Dr. Filip Van Petegem,a professor at UBC. "Our goal is to make them even safer, so patients can benefit without fear of serious side effects."
Sources: University of British Columbia, Nature Communications
