Statin Drugs Cause Muscle Problems by Opening Calcium Channels in Muscle Cells, Study

Statins have been widely used to lower cholesterol and reduce the risk of heart attacks and strokes, saving millions of lives. However, many patients experience muscle-related side effects, ranging from mild pain and weakness to rare but severe muscle breakdown that can cause kidney failure. Researchers at the University of British Columbia (UBC), together with collaborators at the University of Wisconsin-Madison, have identified a key mechanism explaining these muscle problems.

According to a study published in Nature Communications, statins bind to a muscle protein known as the ryanodine receptor (RyR1), which controls the release of calcium inside muscle cells. This receptor acts as a gate that opens to allow calcium release when muscles contract. Statins attach to the receptor and force this gate open abnormally, causing calcium to leak continuously. This leaking calcium is toxic and damages muscle tissue, leading to pain, weakness, and, in some cases, more serious complications.

The team used cryo-electron microscopy to capture how statins interact with RyR1. “We were able to see, almost atom by atom, how statins latch onto this channel,” said lead author Steven Molinarolo. “That leak of calcium explains why some patients experience muscle pain or, in extreme cases, life-threatening complications.” 

The study focused on atorvastatin, a commonly prescribed statin, but the findings likely apply to other drugs in the same class. Unusually, the statins bind as a cluster of three molecules in a pocket of the receptor: one molecule primes the channel by attaching in its closed state, followed by two more molecules forcing it wide open.

Senior author Dr. Filip Van Petegem noted, "This is the first time we've had a clear picture of how statins activate this channel," providing insight to design statins that avoid affecting muscle tissue. By tweaking parts of the statin molecule responsible for the harmful effects, new drugs could maintain cholesterol-lowering benefits while reducing muscle toxicity.

While severe muscle damage is rare among over 200 million statin users globally, mild muscle symptoms like aches and fatigue are more frequent and often cause patients to stop treatment. Understanding this mechanism could help prevent those side effects and improve adherence to important cholesterol-lowering therapies.