Millions of people rely on statins – a medication used to lower cholesterol and reduce the risk of heart attack and stroke. But for some, the drugs come with an unwelcome trade-off: muscle pain, weakness and exercise intolerance that can make it difficult to continue treatment.
Now, researchers at McMaster University have uncovered a biological pathway that may explain why those side-effects occur, opening the door to future therapies that could make statins easier to tolerate while maintaining their life-saving cardiovascular benefits.
Published in Science Advances, the study identifies an immune and metabolic mechanism that drives statin-induced muscle damage, challenging longstanding assumptions about how these side-effects develop.
“Statins are among the most effective medications we have for reducing cardiovascular disease risk and preventing early death,” said Jonathan Schertzer, professor in McMaster’s Department of Biochemistry and Biomedical Sciences and senior author of the study.
“Unfortunately, muscle side-effects lead some people to reduce their dose or stop taking the medication altogether. We wanted to understand why this happens and whether it might be possible to separate the side-effects from the benefits.”
Statin-associated muscle symptoms affect an estimated seven to 29 per cent of people who take the drugs. While researchers have long known that statins can sometimes cause muscle problems, the biological mechanisms behind those effects have remained unclear.
Led by first authors Nazli Robin and Nicole Barra of the Schertzer Lab at McMaster, the team found statins can disrupt how muscle cells produce energy, triggering an immune response that damages muscle tissue. In experiments using muscle cells and mouse models, researchers were able to prevent much of that damage by blocking the immune response.
“One of the most exciting findings of the research is that the mechanism causing muscle side-effects appears to be separate from the mechanism that lowers cholesterol,” said Schertzer. “That suggests it may one day be possible to target the side-effects without interfering with the cardiovascular benefits that make statins so valuable.”
The study also revealed an unexpected link between metabolism and immunity. Researchers found that changes in muscle-cell metabolism triggered an immune response within the cells themselves, providing new insight into how inflammation can contribute to drug side-effects.
Although additional research will be needed before the findings can be translated into therapies for patients, the discovery identifies several potential targets for future drug development aimed at preventing statin intolerance.
“These findings give us a clearer understanding of why some patients experience muscle symptoms and provide promising directions for making these important medications safer and more effective in the future,” added Schertzer.
The study reflects a broad international collaboration which included researchers from the Centre International de Recherche en Infectiologie (CIRI) in Lyon, France; the Centre for Muscle Research at the University of Melbourne, Australia; the Murdoch Children’s Research Institute and The Royal Children’s Hospital in Australia; York University in Canada; and McMaster’s Department of Pathology and Molecular Medicine.
The research was funded by the Natural Sciences and Engineering Research Council of Canada (NSERC).
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For interviews, contact Schertzer directly at schertze@mcmaster.ca.