Millions of people around the world suffer from mysterious muscle pain when taking statins to lower cholesterol, prompting many to stop taking these potentially life-saving drugs.
Studies indicate that approximately 10% of statin users suffer from this muscular syndrome.
Researchers from Columbia and Rochester universities in the United States have revealed the cause of these symptoms, such as pain and fatigue, explaining that they result from the leakage of calcium ions into muscle cells, leading to tissue damage and potentially life-threatening complications.
Statins work by inhibiting an enzyme necessary for cholesterol synthesis in the liver, thereby lowering levels of bad cholesterol (LDL) in the blood.
But these drugs don't just affect cholesterol; they also interact with a protein called ryanodine receptor 1 (RyR1), a channel found in the sarcoplasmic reticulum that surrounds muscle fibers. RyR1 acts as a gatekeeper, opening or closing a calcium channel necessary for normal muscle contraction.
Using mice as models, the researchers tracked how statins bind to RyR1 using cryo-electron microscopy (cryo-EM), a technique that allows for the creation of precise 3D images of biological molecules. They found that some statins, such as simvastatin, may keep these channels open, allowing calcium to leak into the muscles, either directly to destroy tissue or to stimulate muscle-degrading enzymes.
As a result, statin users experience chronic pain, weakness, sensitivity, and muscle spasms. The severity of these symptoms is increased in individuals with RyR1 mutations, who may develop malignant hyperthermia or diaphragmatic dysfunction, affecting lung and respiratory function.
In rare but serious cases, this muscle leakage can lead to rhabdomyolysis, a syndrome in which muscle tissue breaks down and its components enter the bloodstream, causing kidney failure. It can also lead to autoimmune myositis, where the immune system attacks and destroys muscle tissue.
"I have patients who have been prescribed statins, but have refused to take them because of the side effects," says Andrew Marks, a cardiologist at Columbia University's Vagelos College of Physicians and Surgeons. "It's the most common reason patients stop taking these drugs, and it's a real problem that needs a solution."
Researchers point to two promising options for solving the problem: the first is to redesign statins so they do not bind to the RyR1 receptor while retaining their cholesterol-lowering ability. The second option is to use the drug Rycal on statin-intolerant mice, where this drug was able to block leaking RyR1 calcium channels and prevent simvastatin-induced muscle weakness.
The study was published in the Journal of Clinical Investigation.
