New approach aims to safeguard lean muscle during weight-loss therapy
Researchers at the University of Alberta have found that a simple ketone ester supplement could tune weight-loss drugs to preserve lean muscle while still shedding fat. The study centers on semaglutide — the active ingredient in popular drugs like Ozempic, Wegovy and Rybelsus — and explores whether pairing it with ketones can prevent the unwanted shrinkage of skeletal and heart muscle typically seen with this therapy.
Understanding the problem: muscle loss beyond the scale
In initial experiments, the team confirmed that semaglutide can trigger significant skeletal muscle loss, a phenomenon that can account for nearly 40 percent of total weight reduction. More concerning was a parallel finding: the heart also tended to lose muscle mass as patients shed fat. While the heart can shrink as a natural response to weight loss, Dyck notes that some of the cardiac muscle loss appeared independent of overall weight reduction and could have long-term consequences for heart health.
“The question is, if you have a healthy heart, what are the long-term effects of it shrinking more than it should?” said Jason Dyck, a pediatrics professor and Canada Research Chair in Molecular Medicine who led the work. These concerns underscore the need to protect not just the weight loss but the quality of the weight lost—preserving muscle and cardiac function in the process.
Ketones: a natural energy source with protective potential
Ketones are produced by the liver when carbohydrate intake is low or during fasting, and they serve as an alternative energy source for muscles. Recent research has highlighted ketones’ role in preserving skeletal muscle mass. In the Alberta study’s follow-up, the team combined semaglutide with a drinkable ketone ester, designed to raise blood ketone levels similarly to fasting or a ketogenic diet. The goal was to see whether this pairing could prevent muscle loss without compromising fat loss.
Compelling results in animal models
In obese mice, the semaglutide–ketone ester duo delivered dramatic protection. The treated mice experienced less overall body mass reduction, but the fat loss remained similar to the group receiving semaglutide alone. Crucially, the ketone combination prevented loss of both skeletal muscle and cardiac muscle—a strong indication that the intervention supports lean body composition rather than simply accelerating weight loss.
“It turns out it does a fantastic job in protecting from muscle loss — skeletal muscle loss and loss of cardiac mass,” Dyck explains. “It really just fine-tunes, potentially, this therapy.”
Mechanism: mitochondria as the key to preservation
The protective effect appears to hinge on mitochondria, the energy factories of the cells. Semaglutide can impair mitochondrial function, reducing the energy available to muscles and triggering proteolysis. Ketones, in contrast, seem to keep mitochondria more active and healthier, enabling muscles to resist breakdown even as fat stores are mobilized.
From animals to humans: planning clinical trials
The Alberta team has secured a Transformational Medical Research Grant to translate these findings into human studies, aiming to determine whether ketone supplementation can safely and effectively preserve muscle mass in people using semaglutide. The researchers emphasize that the goal is not to halt fat loss but to ensure the body’s lean tissues are protected during therapy.
Implications for millions using semaglutide therapies
With semaglutide-based drugs now widely prescribed for obesity and metabolic disease, a practical strategy to minimize lean tissue loss could improve long-term outcomes and quality of life for patients. If human trials confirm the animal data, ketone supplements could become an important adjunct to weight-loss regimens, helping patients shed fat while maintaining heart and skeletal muscle health.
Support and future directions
The research received support from the Canadian Institutes of Health Research, the Stollery Children’s Hospital Foundation, and Alberta Women’s Health Foundation, among others. The University of Alberta team plans to begin human testing after securing regulatory approvals, with a vision toward integrating ketone supplementation into standard care for patients on semaglutide therapies.
