For millions of people, statins are a daily shield against heart disease.But around 10 percent of those who take statins to lower cholesterol experience a mysterious, painful side effect that causes many to discontinue these potentially life-saving medicines.Scientists have recently found one possible reason why.Research from Columbia University and the University of Rochester in the US revealed a potential culprit: a tiny calcium gate inside muscle cells that statins may force open.The resulting calcium leak can damage muscle tissue, offering a new explanation for at least some cases of statin-associated muscle symptoms (SAMS)."I've had patients who've been prescribed statins, and they refused to take them because of the side effects," said lead author Andrew Marks, a cardiologist at the Columbia University Vagelos College of Physicians and Surgeons.Statins work by blocking an enzyme that's required for the biosynthesis of cholesterol in the liver.As a result, levels of 'bad' LDL cholesterol are reduced in the blood, helping to prevent one of America's top killers: cardiovascular diseases like atherosclerosis, the buildup of fatty deposits in blood vessels.But statins also affect "off-target" molecules, including a protein called ryanodine receptor 1 (RyR1). RyR1 is a mushroom-shaped channel, or gate, located on the sarcoplasmic reticulum, a web-like structure that surrounds muscle fibers.RyR1 acts like a bouncer at a club, opening or closing the door to let calcium ions flow into the muscles. This calcium flow is an essential process that mediates muscle contractions.Structure of RyR1, a protein channel that allows calcium to leak into muscles. (Wenbo Chen/Chen & Kudryashev, EMBO Rep., 2020)Using mice as models, the researchers observed the precise way statins bind to RyR1, using an imaging technique called cryo-electron microscopy (cryo-EM).Cryo-EM involves flash-freezing biological samples and then blasting them with electron beams. The deflection pattern of the electrons reveals tiny structures, allowing scientists to create highly detailed 3D images of things like proteins and view their constituent molecules.Yet cholesterol-lowering drugs like simvastatin may keep these gates open, allowing calcium ions to leak into muscle cells, which can either directly damage muscles or trigger enzymes that degrade them.As a result, statin users may experience persistent pain, weakness, tenderness, and cramps.The issue is exacerbated in individuals with RyR1 mutations, who may also experience episodes of malignant hyperthermia (a severe overheating triggered by medication) or weakness in the diaphragm that leads to reduced lung function and respiratory disorders.In rare but potentially life-threatening cases, the side effects of statins can induce rhabdomyolysis, a serious syndrome in which muscle tissues rupture and leak into the bloodstream, culminating in kidney failure.The equally gruesome autoimmune-mediated necrotizing myositis may also rarely occur, a condition in which the immune system turns against its own tissues and kills muscle tissue.The leaky calcium gate explanation may not apply to all cases of SAMS, but now that we understand this mechanism, it could help identify people at risk of statin intolerance.Simvastatin molecules bind to ryanodine receptors on a muscle protein. The flow of calcium through the opened channels in the receptors could explain the muscular side effects of statins. (Columbia University)Around 40 million adults take statins in the US alone, and approximately 10 percent of treated individuals experience SAMS."It's the most common reason patients quit statins, and it's a very real problem that needs a solution," said Marks.Related: US Cardiologists Have Published New Guidelines For Managing CholesterolThe researchers highlight two promising options. The first is to redesign statins so they don't bind to RyR1 but still inhibit cholesterol production in the liver.Alternatively, when the researchers treated statin-intolerant mice with Rycal, an experimental class of drug used to treat patients with rare muscle diseases, they were able to close the leaky RyR1 calcium gates and prevent simvastatin-induced muscle weakness."It is unlikely that this explanation applies to everyone who experiences muscular side effects with statins," Marks explained."But even if it explains a small subset, that's a lot of people we could help if we can resolve the issue."This research was published in the Journal of Clinical Investigation.An earlier version of this article was published in February 2026.