Glucagon-like peptide-1 receptor agonists (GLP-1RAs) like semaglutide are highly effective in treating obesity, but up to 45% of the resulting weight loss may be muscle, which has led to opportunities for product formulators to protect muscle mass.
New data published in JCI insight suggests that co-administration of semaglutide and a β-hydroxybutyrate–generating ketone ester for three weeks prevented semaglutide-induced changes in gene expression related to mitochondria and muscle atrophy.
“Together, these findings demonstrate that ketone ester supplementation can maintain muscle mass and performance during semaglutide-driven weight loss,” wrote researchers from the University of Alberta in Canada.
“These preclinical findings support ketone therapy as a promising strategy to counteract the sarcopenia-promoting effects of GLP-1RAs and warrant clinical evaluation to assess its translational potential.”
Expert: “Excellent mechanistic data”
Commenting independently on the new study, Dr. David Church, director of the Center for Translational Research in Aging and Longevity at the University of Arkansas for Medical Sciences (UAMS), called the new study a “great effort, but still a mechanistic animal study”.
Dr. Church said that it was important to keep in mind the metabolic difference between the two species, especially when you consider a human has a greater percentage of muscle mass (and therefore more to give up) relative to total body mass as compared to a mouse. A mouse has a larger percentage of internal organs relative to total body mass, he added.
“That said, this data provides excellent mechanistic data. The researchers demonstrated that co-administering an oral ketone ester with semaglutide successfully preserved skeletal muscle mass, grip strength, and treadmill endurance in obese mice, all without compromising fat loss,” he said. “Mechanistically, semaglutide monotherapy suppressed mitochondrial gene expression and elevated atrophy-related genes. However, the ketone treatment effectively prevented the downregulation of key ketolytic enzymes (BDH1 and SCOT) and stabilized mitochondrial electron transport chain expression. This suggests that during the severe caloric deficit induced by semaglutide, exogenous ketones maintain mitochondrial flux and potential energy production from lipids, ketones, etc. This is key as protein turnover is energetically expensive.
“Further, there are some acute tracer studies supporting the notion that ketones can be anabolic during periods of low caloric intake. In that regard, it is nice to see results in alignment. Regardless, the next step I would love to see is a longer trial of either a 12-week RCT or a week-long D2O tracer study to get a little bit better idea of how this treatment paradigm would work in humans. Nonetheless, it is an encouraging study and data.”
Study details
The Alberta-based scientists fed eight-week-old male mice a high fat diet for 15-17 weeks to induce obesity and then switched to a regular chow diet running at a 500-kcal deficit per day. The mice were randomly divided into three groups, all of which received daily injections for three more weeks: The first group received phosphate buffered saline (control), the second received semaglutide, and the third received semaglutide plus ketone ester in their drinking water.
Results showed that semaglutide alone led to significant loss of muscle mass and strength, while mitochondrial gene expression was suppressed. On the other hand, the genes for atrophy of skeletal muscle were elevated.
These changes were prevented when ketone esters were added to the protocol, without affecting the fat loss results, said the researchers.
“Given the potential harmful consequences of semaglutide-induced muscle loss, our findings support investigating the muscle-preserving effects of ketone therapy in clinical trials involving semaglutide for weight loss,” wrote the researchers.
“Because ketone therapy has already been evaluated in multiple clinical trials for other indications, where it was shown to be safe and well tolerated, the rapid translation of this approach could meaningfully improve the health and well-being of millions of people using semaglutide and related GLP-1RAs.”
Source: JCI insight, doi: 10.1172/jci.insight.201810. “Semaglutide-induced loss of skeletal muscle mass is blunted by co-administration of ketone esters”. Authors: Y. Abuetabh, et al.
