Millions of Americans currently take GLP-1 drugs such as Ozempic and Wigovy for weight loss. But along with fat, many people are quietly losing something else: muscle. Unlike fat, muscle doesn’t come back quickly, so muscle loss can negatively impact your strength, mobility, and overall health.
Now, researchers at Stanford Medicine have discovered that an existing drug already in clinical trials for age-related muscle loss may be able to alleviate this problem. Young adult mice given the drug in combination with GLP-1 showed improved muscle regeneration and muscle strength recovery after muscle injury without compromising fat loss.
There is a significant unmet need for drugs that help maintain muscle health and strength in GLP-1 users. We believe this compound, which has been deemed safe by the Food and Drug Administration, has promise for this indication. ”
Dr. Helen Blau, Professor of Microbiology and Immunology, Stanford University
Blau, director of the Baxter Institute for Stem Cell Biology and Donald E. Baxter and Delia B. Baxter Foundation Professor, is the senior author of the study, which was published June 2. Proceedings of the National Academy of Sciences.
Blau’s research has long focused on muscle stem cells, the regenerative cells the body needs to repair and rebuild muscle after intense training or injury. In 2021, her group identified an enzyme called 15-PGDH. This enzyme increases temporarily after injury and permanently increases with age, becoming more prevalent. They believe that 15-PGDH may be key to regeneration because it limits the availability of prostaglandin E2, a metabolite essential for muscle stem cell activation, which is one reason why older people have difficulty building muscle strength.
In untraumatized aged mice, blocking the enzyme with an inhibitor not only improves muscle mass and strength, but also reverses cartilage loss in aged mice and prevents the development of post-traumatic osteoarthritis. Oral PGDHi is already in clinical trials to treat age-related muscle loss.
Preservation of muscle building mechanisms
In the new study, Blau’s team tested whether the PGDHi drug could promote muscle repair and counteract the weight loss that occurs during GLP-1-induced weight loss by increasing prostaglandin E2 and activating muscle stem cells.
The researchers fed young adult male mice a high-fat diet for 12 weeks to induce obesity, then administered semaglutide (Ozempic or Wegovy), experimental PGDHi, or both for five weeks.
Obese mice treated with semaglutide lost about 25% of their body weight and had significantly reduced fat levels. Semaglutide also decreased skeletal muscle mass. Under normal conditions, muscle loss does not lead to decreased strength, but the situation changes when the muscles are stressed. This animal’s muscles did not recover well after injury.
“Not only did GLP-1 receptor agonists cause initial muscle loss, but they also reduced the ability of young mice to regenerate muscle,” said Dr. Minas Nalbandian, a postdoctoral fellow in Blau’s lab and first author of the new paper. “It is critical that muscle stem cells are activated to repair and build muscle, even after injury or routine exercise. PGDHi enhanced that regenerative response even in the context of semaglutide-induced weight loss.”
In young animals treated with both semaglutide and the PGDHi drug, the size of regenerating muscle fibers was restored and the muscles became stronger after injury compared to mice treated with semaglutide alone and even to untreated mice. PGDHi promoted muscle stem cell proliferation and restored the ability to generate new muscle fibers.
However, when the researchers administered PGDHi alone to young, healthy mice, it had no effect on muscle strength, confirming that PGDHi is not a muscle-building drug in young mice unless there is muscle damage. The benefits only appear after injury or, as the researchers hypothesize, after regular exercise.
“What we’re seeing is an increased ability to regenerate muscle, which really speaks to how well you can rebuild muscle after an injury,” Nalbandian said. “Exercise and everyday use place repeated adaptive demands on muscles. This is relevant not only to recovery from major injuries, but also to the biology of muscle repair and maintenance during physical activity.”
Candidate drugs already in clinical trials
The experimental PGDHi compound MF-300 has already completed Phase 1 clinical trials, confirming its safety in humans, and is scheduled for a Phase 2B trial for age-related muscle loss (called sarcopenia) later this year. New research suggests that the same compound may also help people who are taking GLP-1 drugs or who are undergoing significant weight loss without taking GLP-1.
“When you lose a lot of weight, you often lose some of your lean body mass along with the fat,” Blau says. “The effects we’re seeing with GLP-1 are not specific to that drug, but to general caloric restriction.”
Ultimately, Blau hopes PGDHi will become a standard combination of GLP-1 drugs, allowing patients to lose weight without sacrificing muscle.
“We are trying to address a serious and undesirable side effect of GLP-1 drugs, which is muscle loss along with fat gain,” Blau said.
He points out that the drug has not yet been tested in older obese people, who have different risk factors for muscle loss.
Researchers from the University of California, Davis and Ark Research Institute contributed to the study.
This research was supported by the Baxter Foundation, the Milky Way Research Foundation, the Stanford Heart and Vascular Institute Seed Grant Award, the Stanford BioX Summer Undergraduate Research Program, the National Institutes of Health (grants R01AG02096115, R01AG069858-01, R01DK125260, P30DK116074 and RHG009674A), the American Heart Association, the Arc Institute, and the NIH Pathway to Independence Award (grants K99AR081618).
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Reference magazines:
Nalbandian, M. Others. (2026). 15-PGDH inhibition promotes muscle repair and strength recovery during GLP-1 receptor agonist-induced weight loss. Proceedings of the National Academy of Sciences. DOI: 10.1073/pnas.2606533123. https://www.pnas.org/doi/10.1073/pnas.2606533123
