Many people stop taking cholesterol-lowering statins because they experience muscle aches, weakness, and fatigue.
A new study by Columbia researchers now suggests that at least for some people, the side effects arise when statins bind to a protein in muscle cells and cause a leak of calcium ions inside the cells.
"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," says Andrew Marks, chair of the Department of Physiology and Cellular Biophysics at the Vagelos College of Physicians and Surgeons.
About 40 million adults in the U.S. take statins to lower cholesterol, and about 10% experience these muscular side effects.
"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," says Marks.
Electron microscopy pinpoints statin-muscle interaction
Statins' muscular side effects have puzzled researchers since the drugs hit the market in the late 80s. Statins are designed to lower cholesterol by binding to an enzyme involved in cholesterol synthesis. But statins also bind to other "off-target" molecules, and some previous studies have suggested that muscular side effects occur when statins bind to a specific protein in muscle.
With cryo-electron microscopy, a technique that can image molecules down to individual atoms, the researchers of the new study documented this binding and uncovered the precise details of the interaction.
Simvastatin molecules bind to two locations on a muscle protein, called the ryanodine receptor, which opens a channel in the receptor. The flow of calcium through the open channel could explain the muscular side effects of statins.
The images revealed two locations on the muscle protein, called the ryanodine receptor, where a statin called simvastatin binds, opening a channel in the receptor and allowing calcium to flow through.
The calcium leak could explain the muscular side effects of statins, Marks says, by weakening the muscle directly or by activating enzymes that degrade muscle tissue.
Building a better statin
The new images also suggest that statins could be redesigned so they do not bind the ryanodine receptor but retain their cholesterol-lowering ability.
Marks is now collaborating with chemists to create such a statin.
Plugging the calcium leak could be another option: Statin-induced calcium leaks in mice can be closed, the researchers showed, with an experimental drug developed in the Marks lab for other conditions involving calcium leaks.
These drugs are currently being tested in people with rare muscle diseases. If it shows efficacy in those patients, we can test it in statin-induced myopathies," Marks says
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Andrew Marks is also the Clyde and Helen Wu Professor of Medicine at Columbia University Vagelos College of Physicians and Surgeons, professor of biomedical engineering, and director of the Wu Center for Molecular Cardiology.
The results were published Dec. 15 in "Structural basis for simvastatin-induced skeletal muscle weakness associated with RyR1 T4709M mutation," in the Journal of Clinical Investigation.
All authors (from Columbia unless noted): Gunnar Weninger, Haikel Dridi, Steven Reiken, Qi Yuan, Nan Zhao (University of Rochester), Linda Groom (University of Rochester), Jennifer Leigh (University of Rochester), Yang Liu, Carl Tchagou, Jiayi Kang, Alexander Chang, Estefania Luna-Figueroa, Marco C. Miotto, Anetta Wronska, Robert T. Dirksen (University of Rochester), and Andrew R. Marks.
The research was supported by grants from the NIH (R01HL145473, R01DK118240, R01HL142903, R01HL140934, R01NS114570, R01AR070194, R01AR078000 , R25HL156002, R25NS076445, P01HL164319, and T32HL120826.
Andrew Marks owns stock in RyCarma Therapeutics Inc., a company developing compounds targeting the ryanodine receptor, and a coinventor on U.S. patent nos. US8022058 and US8710045. Gunnar Weninger, Haikel Dridi, Marco Miotto, and Andrew Marks are inventors on the patent application entitled "STATIN INNOVATION FOR MUSCLE-FRIENDLY CHOLESTEROL MANAGEMENT" [Invention Report (IR) #CU24350] to be filed by Columbia University.
