Many people who take statins to lower cholesterol report muscle aches, weakness, and fatigue, which often leads them to stop using the medication. A new study from Columbia University Vagelos College of Physicians and Surgeons provides insight into why these side effects occur for some patients.
Researchers at Columbia have found that statins can bind to a protein in muscle cells, causing a leak of calcium ions inside the cells. Andrew Marks, chair of the Department of Physiology and Cellular Biophysics at the Vagelos College of Physicians and Surgeons, said, “It is unlikely that this explanation applies to everyone who experiences muscular side effects with statins, but even if it explains a small subset, that’s a lot of people we could help if we can resolve the issue.” He added, “I’ve had patients who’ve been prescribed statins, and they refused to take them because of the side effects. It’s the most common reason patients quit statins, and it’s a very real problem that needs a solution.”
About 40 million adults in the United States use statins for cholesterol management. Of those users, roughly 10% experience muscle-related side effects.
Statin-induced muscle symptoms have been an unresolved question since these drugs became widely available in the late 1980s. While statins are designed to lower cholesterol by targeting an enzyme involved in its synthesis, they also interact with other molecules in the body. Previous studies have suggested that when statins bind to certain proteins in muscles, this may lead to adverse effects.
The Columbia research team used cryo-electron microscopy—a method capable of imaging molecules at atomic resolution—to observe how simvastatin binds directly to two sites on a muscle protein called the ryanodine receptor. This binding opens a channel within the receptor and allows calcium ions to flow through. The resulting calcium leak could weaken muscles or activate enzymes that break down muscle tissue.
According to Marks, “The calcium leak could explain the muscular side effects of statins…by weakening the muscle directly or by activating enzymes that degrade muscle tissue.”
The findings indicate potential paths forward for reducing or eliminating these side effects. One approach is redesigning statin drugs so they do not bind with ryanodine receptors while maintaining their cholesterol-lowering properties. Marks is currently working with chemists toward this goal.
Another possibility involves closing the calcium leak itself. The researchers showed that an experimental drug developed in Marks’ laboratory can close such leaks in mice. This drug is already being tested in people with rare muscle diseases; if successful there, it may be evaluated for use against statin-induced myopathies as well. “If it shows efficacy in those patients,” Marks said,”we can test it in statin-induced myopathies.”
Andrew Marks holds several positions at Columbia University Vagelos College of Physicians and Surgeons: Clyde and Helen Wu Professor of Medicine; professor of biomedical engineering; director of the Wu Center for Molecular Cardiology.
The study was published December 15th in The Journal of Clinical Investigation. Authors include Gunnar Weninger, Haikel Dridi, Steven Reiken, Qi Yuan (Columbia), Nan Zhao (University of Rochester), Linda Groom (University of Rochester), Jennifer Leigh (University of Rochester), Yang Liu (Columbia), Carl Tchagou (Columbia), Jiayi Kang (Columbia), Alexander Chang (Columbia), Estefania Luna-Figueroa (Columbia), Marco C. Miotto (Columbia), Anetta Wronska (Columbia), Robert T. Dirksen (University of Rochester) and Andrew R. Marks.
This research received support from multiple NIH grants: R01HL145473; R01DK118240; R01HL142903; R01HL140934; R01NS114570; R01AR070194; R01AR078000 ; R25HL156002; R25NS076445; P01HL164319; T32HL120826.
Disclosures include Andrew Marks’ stock ownership in RyCarma Therapeutics Inc., which develops compounds targeting ryanodine receptors, as well as his status as co-inventor on related U.S patents US8022058 and US8710045. Several authors—Gunnar Weninger, Haikel Dridi, Marco Miotto and Andrew Marks—are inventors on a pending patent application entitled “STATIN INNOVATION FOR MUSCLE-FRIENDLY CHOLESTEROL MANAGEMENT” [Invention Report #CU24350] through Columbia University.
