In young animals that were treated with both semaglutide and a PGDHi drug, regenerating muscle fiber size was restored, and muscles were stronger after injury compared with mice on semaglutide alone — or even untreated mice. The PGDHi boosted the proliferation of muscle stem cells and restored their ability to generate new muscle fibers.

But when the researchers gave young, healthy mice PGDHi on its own, it had no effect on muscle strength, confirming that in young mice PGDHi isn’t a muscle-building drug unless there is muscle injury. Its benefits occur only after damage or, the researchers postulate, after regular exercise.

“What we’re seeing is increased muscle regenerative capacity, which is really a proxy for how well you can rebuild muscle after an injury,” Nalbandian said. “Exercise and daily use place repeated adaptive demands on muscle. This isn’t just about recovering from major injuries, but also about the biology of muscle repair and maintenance when physically active.”

A candidate drug already in clinical trials

An experimental PGDHi compound, MF-300, has already completed Phase 1 clinical trials and been found safe in humans, with Phase 2b trials for age-related muscle loss (called sarcopenia) planned later this year. The new study suggests that the same compound may be useful in people on GLP-1 medications — or even those undergoing significant weight loss without a GLP-1.

“When people lose substantial weight, some lean mass is often lost along with fat,” Blau said. “The effect we’re seeing with GLP-1s isn’t unique to the drugs, but to caloric restriction in general.”

Ultimately, Blau hopes that a PGDHi could become a standard companion to GLP-1 drugs, letting patients lose weight without sacrificing muscle.

“We’re on the way to tackling a major and unwanted side effect of GLP-1 drugs: losing muscle strength along with fat,” Blau said.

She notes that the drugs have yet to be tested in older obese individuals, who have different risk factors for muscle loss.

Researchers from the University of California, Davis, and the Arc Institute contributed to the study.

The research was supported by the Baxter Foundation, the Milky Way Research Foundation, a Stanford Cardiovascular Institute Seed Grant award, the Stanford Bio-X 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 an NIH Pathway to Independence Award (grant K99AR081618).