Statins remain a cornerstone of cardiovascular disease prevention, having saved millions of lives by lowering cholesterol and reducing the incidence of heart attacks and strokes. Despite their proven efficacy, a subset of patients experiences adverse muscular effects, ranging from mild pain and weakness to rare but severe muscle breakdown that can lead to kidney failure.
Scientists at the University of British Columbia (UBC), in collaboration with researchers at the University of Wisconsin–Madison, have identified a molecular mechanism that explains these complications. Published in Nature Communications, the findings provide a structural blueprint for developing next-generation statins that retain lipid-lowering benefits while minimizing muscle toxicity.
How Statins Trigger a Harmful Calcium Leak
Using cryo-electron microscopy—a high-resolution imaging technique that visualizes protein structures at near-atomic detail—the team investigated the ryanodine receptor (RyR1), a critical calcium-release channel in skeletal muscle cells. Under normal physiology, RyR1 acts as a tightly regulated gate, releasing calcium to initiate muscle contraction. The researchers discovered that statins bind to this channel and lock it in an open conformation, causing uncontrolled calcium leakage into the cytoplasm. This dysregulation creates a cytotoxic environment that damages muscle fibers.
“We were able to see, almost atom by atom, how statins latch onto this channel,” said lead author Dr. Steven Molinarolo, a postdoctoral researcher in UBC’s Department of Biochemistry and Molecular Biology. “That persistent calcium leak explains why some patients experience muscle pain or, in extreme cases, life-threatening rhabdomyolysis.”
Three Statin Molecules Reveal the Mechanism Behind Muscle Damage
The study focused primarily on atorvastatin, a widely prescribed statin, though the mechanism likely extends across the drug class. A striking finding was the cooperative binding mode: three statin molecules occupy a single pocket on the receptor. The first molecule binds while the channel is closed, priming it to open. Two subsequent molecules then stabilize the open state, sustaining the pathological calcium efflux.
“This is the first time we’ve had a clear picture of how statins activate this channel,” said senior author Dr. Filip Van Petegem, a professor at UBC’s Life Sciences Institute. “It provides a roadmap for designing statins that avoid interaction with skeletal muscle tissue altogether.”
This structural insight enables rational drug design. By modifying the specific molecular moieties responsible for RyR1 binding, medicinal chemists can potentially decouple the cholesterol-lowering activity from the off-target muscle effects.
A Potential Path Toward Safer Cholesterol Drugs
With over 200 million people worldwide prescribed statins, muscle-related side effects—though severe in only a small fraction—are a leading cause of treatment discontinuation. Even mild myalgia can compromise adherence, leaving patients vulnerable to cardiovascular events. The current discovery lays the groundwork for better-tolerated therapies that preserve the cardiovascular protection patients rely on.
Achieving this mechanistic clarity required state-of-the-art instrumentation at UBC’s high-resolution macromolecular cryo-EM facility. The resulting structural data bridges a long-standing clinical observation with a defined molecular pathway, offering a concrete target for future pharmaceutical development.
“Statins have been a cornerstone of cardiovascular care for decades,” Dr. Van Petegem noted. “Our goal is to make them even safer, so patients can benefit without fear of serious side effects.”
While further research and clinical translation are necessary, these findings chart a promising trajectory. For the millions dependent on statin therapy, future agents with reduced myotoxicity could significantly improve treatment persistence and quality of life.