Scientists Finally Crack Decades-Old Mystery Behind Statins’ Painful Side Effects

Statins are common drugs used to lower the risk of heart attacks and strokes. However, about one in ten people who take them experience muscle pain, fatigue, and weakness. These side effects can be so severe that patients stop taking the medication.

New research from Columbia University and the University of Rochester helps explain why this happens. Their findings show that statins can disrupt how muscle cells handle calcium. This discovery offers a clearer reason for statin-associated muscle symptoms (SAMS) and suggests new ways to prevent them.

How Statins Affect Muscles

Statins work by blocking an enzyme in the liver that makes cholesterol. This lowers "bad" cholesterol (LDL) and helps prevent atherosclerosis, where fatty deposits build up in blood vessels. But statins don't just affect the liver. They also interact with other proteins in the body, including one important for muscle function.

This protein is called ryanodine receptor 1 (RyR1). It's found inside muscle cells in a network called the sarcoplasmic reticulum, which stores calcium. Normally, RyR1 carefully controls when calcium is released, allowing muscles to contract and relax smoothly. Even small problems with this system can cause noticeable effects because calcium signaling is key to almost every muscle movement.

Researchers used mice and high-resolution cryo-electron microscopy to see how statins interact with RyR1. This imaging method freezes biological samples quickly and uses electron beams to create detailed 3D pictures at a molecular level.

The team found that certain statins, like simvastatin, can bind to RyR1 and make the channel unstable. Instead of opening only when needed, the channel becomes "leaky." This allows calcium to continuously seep into muscle cells. Too much calcium can damage muscle fibers or activate enzymes that break them down.

Simvastatin molecules bind to two spots on the ryanodine receptor, opening a channel. Calcium flow through this channel might explain muscle side effects. Credit: Columbia University

This leads to symptoms like soreness, cramping, tenderness, and reduced strength. For some people, especially those with genetic changes affecting RyR1, the problems can be more serious. These might include malignant hyperthermia, a dangerous rise in body temperature, or breathing difficulties due to impaired diaphragm function.

In rare cases, muscle damage can lead to rhabdomyolysis, where muscle tissue breaks down and releases its contents into the bloodstream, potentially causing kidney failure. Another rare but severe reaction is autoimmune-mediated necrotizing myositis, where the immune system attacks muscle tissue by mistake.

Finding Solutions for Statin Side Effects

This calcium leak mechanism doesn't explain every case of statin intolerance, but it's a big part of the puzzle. About 40 million adults in the U.S. take statins, so even a partial explanation can have a huge impact.

Andrew Marks, a cardiologist at Columbia University, noted that many patients refuse to take statins because of side effects. He called it the most common reason patients stop statins and a "very real problem that needs a solution."

The findings point to two promising solutions. One idea is to redesign statins so they still lower cholesterol but don't interfere with RyR1.

Another approach is to protect muscle cells directly. In the study, researchers tested experimental drugs called Rycals in mice that couldn't tolerate statins. These compounds helped stabilize the calcium channel, stopping leaks and reducing muscle weakness.

Deep Dive & References: Cryo-electron microscopy reveals sequential binding and activation of Ryanodine Receptors by statin triplets - Nature Communications, 2025