Millions of people worldwide depend on statins to lower cholesterol and protect their heart health, but many stop taking these life-saving drugs due to uncomfortable muscle pain, weakness, and fatigue. Recent research has finally identified the molecular mechanism behind these side effects, offering hope for safer cholesterol medications in the future.
Two separate research teams have independently uncovered how statins trigger muscle problems. Scientists at the University of British Columbia and Columbia University both used advanced imaging technology to reveal that statins bind to a critical muscle protein, causing harmful calcium leaks inside muscle cells. These discoveries could reshape how cholesterol drugs are designed and allow patients to benefit from treatment without debilitating side effects.
Understanding the Muscle Connection
About 40 million adults in the United States take statins to control cholesterol levels, with roughly 10 percent developing muscle-related complications. While these symptoms are generally mild for most patients, they represent the most common reason people abandon their prescriptions. In rare cases, statins can cause severe muscle breakdown that may lead to kidney failure.
Statins work by targeting an enzyme involved in cholesterol production, but they also attach to other unintended molecules in the body. Scientists have suspected for years that muscle side effects occur when statins interact with muscle tissue, but the precise details of this interaction remained unclear until now.
Breakthrough Imaging Reveals Calcium Leaks
Researchers at both universities used cryo-electron microscopy, a powerful technique that visualizes proteins at near-atomic detail, to observe exactly how statins interact with muscle cells. This advanced imaging allowed them to see molecular structures down to individual atoms.
The Columbia team, led by Andrew Marks, chair of the Department of Physiology and Cellular Biophysics at the Vagelos College of Physicians and Surgeons, focused on simvastatin. They discovered that this commonly prescribed statin binds to two specific sites on a muscle protein called the ryanodine receptor. This binding opens a channel in the protein, allowing calcium ions to leak into areas where they do not normally flow.
The UBC research team, headed by Dr. Filip Van Petegem and lead author Dr. Steven Molinarolo, examined atorvastatin, another widely used statin. They found that three statin molecules cluster together inside a pocket of the ryanodine receptor. The first molecule attaches when the channel is closed, priming it to open, while two additional molecules wedge in and force the channel fully open.
How Calcium Causes Damage
The ryanodine receptor acts as a gatekeeper for calcium inside muscle cells, opening only when muscles need to contract. When statins force this gate open continuously, calcium leaks out in a toxic flow that can damage muscle tissue. According to the research, this excess calcium either weakens muscle fibers directly or activates enzymes that gradually break down muscle tissue over time.
Marks noted that while this explanation may not apply to everyone experiencing muscle side effects from statins, even if it accounts for a subset of cases, that represents a significant number of people who could be helped. He emphasized that many patients refuse to take prescribed statins specifically because of side effects, making this a very real problem requiring a solution.
Designing Safer Cholesterol Drugs
Both research teams believe their findings provide a roadmap for developing statins that lower cholesterol without causing muscle damage. By modifying only the parts of statin molecules responsible for binding to the ryanodine receptor, scientists could preserve cholesterol-lowering benefits while eliminating harmful interactions with muscle tissue.
Marks is currently collaborating with chemists to create redesigned statins that avoid unwanted interactions with the ryanodine receptor. Van Petegem echoed this optimism, stating that having a clear picture of how statins activate the calcium channel represents a significant step forward.
Alternative Treatment Approaches
Another potential strategy involves stopping the calcium leak itself rather than redesigning the statin molecule. The Columbia researchers demonstrated that statin-induced calcium leaks in mice can be closed using an experimental drug developed in the Marks laboratory for other disorders involving abnormal calcium flow. These drugs are currently undergoing testing in people with rare muscle diseases, and if they prove effective in those patients, they could be tested for statin-induced muscle problems.
While severe muscle damage affects only a small fraction of the more than 200 million statin users worldwide, milder symptoms like soreness and fatigue are far more common and frequently cause patients to discontinue treatment. These new findings could help prevent such problems and improve adherence to therapies that protect cardiovascular health.
The Columbia study was published in the Journal of Clinical Investigation, while the UBC research appeared in Nature Communications. Both teams emphasized that advanced imaging technology played a crucial role in turning longstanding questions about drug safety into actionable scientific insights that could shape future therapies. For millions who rely on statins, these breakthroughs may translate into fewer muscle problems and better quality of life.
