Around 10 percent of individuals prescribed statins, a common medication for lowering cholesterol, report experiencing unexplained muscle pain. This side effect has led many to discontinue what could be life-saving treatment. Recent research conducted by scientists at Columbia University and the University of Rochester has finally shed light on the underlying mechanism of these muscle symptoms.
The research team discovered that statin-associated muscle symptoms (SAMS), which include persistent aches and fatigue, are linked to an influx of calcium into muscle cells. This influx can cause tissue damage and potentially severe health complications. Statins function by inhibiting an enzyme critical for cholesterol production in the liver. By doing so, they effectively reduce levels of harmful LDL cholesterol in the bloodstream, thereby decreasing the risk of cardiovascular diseases, including atherosclerosis.
In their study, the researchers found that statins also interact with certain “off-target” molecules, particularly a protein known as ryanodine receptor 1 (RyR1). This protein acts as a channel on the sarcoplasmic reticulum, a structure that surrounds muscle fibers. RyR1 regulates the flow of calcium ions into muscle cells, a vital process for muscle contraction.
Using advanced imaging techniques such as cryo-electron microscopy (cryo-EM), the team observed how statins bind to RyR1. Cryo-EM allows scientists to capture high-resolution 3D images of biological structures by flash-freezing samples and bombarding them with electron beams. This method revealed that statins like simvastatin may keep RyR1 channels open longer than intended, permitting excess calcium to enter muscle cells. This leakage can either directly harm muscle tissue or activate enzymes that lead to further degradation.
Individuals with mutations in the RyR1 gene may be at higher risk for severe reactions to statins, including episodes of malignant hyperthermia—a dangerous increase in body temperature triggered by certain medications—or respiratory issues due to diaphragm weakness. In rare cases, statins can cause serious conditions such as rhabdomyolysis, where muscle tissue breaks down and releases harmful substances into the bloodstream, potentially resulting in kidney failure. Autoimmune-mediated necrotizing myositis, a condition where the immune system attacks muscle tissue, is another severe but infrequent side effect.
While the new findings may not explain all instances of SAMS, they provide valuable insight into identifying individuals who may be intolerant to statins. Approximately 40 million adults in the United States use statins, with 10 percent of them experiencing SAMS. “I’ve had patients who’ve been prescribed statins, and they refused to take them because of the side effects,” said Andrew Marks, a cardiologist at Columbia University Vagelos College of Physicians and Surgeons. “It’s the most common reason patients quit statins, and it’s a very real problem that needs a solution.”
The researchers propose two potential solutions to mitigate these adverse effects. One approach involves redesigning statins so they do not bind to RyR1 while still effectively inhibiting cholesterol production. Another strategy tested on mice involved administering an experimental drug known as Rycal, which successfully closed the leaky RyR1 calcium channels and prevented statin-induced muscle weakness.
The results of this research were published in the Journal of Clinical Investigation, marking a significant advancement in understanding the complexities of statin-related muscle symptoms and paving the way for improved treatments in the future.
