Existing drug mitigates muscle loss from GLP-1 medications

Millions of Americans are currently taking GLP-1 medications such as Ozempic or Wegovy for weight loss. But along with the fat, many are quietly losing something else: muscle. Unlike fat, muscle doesn't return quickly, and muscle loss can have deleterious effects on strength, mobility and overall health.

Now, Stanford Medicine researchers have found that an existing drug, already in clinical trials for age-related muscle loss, might mitigate this problem. Young adult mice receiving the drug alongside a GLP-1 exhibited improved muscle regeneration and recovery of strength after muscle damage without undermining fat loss.

There is a major unmet need for a drug that can help GLP-1 users preserve their muscle health and strength. We think this compound, which has been deemed safe by the Food and Drug Administration, holds promise for this indication."

Helen Blau, PhD, professor of microbiology and immunology, Stanford Medicine

Blau, who directs the Baxter Laboratory for Stem Cell Biology and is the Donald E. and Delia B. Baxter Foundation Professor, is the senior author of the research, which was published on June 2 in Proceedings of the National Academy of Sciences.

Blau's research has long focused on muscle stem cells, the regenerative cells needed for the body to repair and rebuild muscle after an intense workout or injury. In 2021, her group identified an enzyme, called 15-PGDH, which transiently increases after injury and becomes constitutive and more prevalent with age. They believe 15-PGDH may hold the key to regeneration as it limits the availability of a metabolite, prostaglandin E2, which is essential for activation of muscle stem cells - offering one reason it is harder for older adults to increase their strength.

In older mice in the absence of injury, blocking the enzyme with an inhibitor not only boosts muscle mass and strength, but also reverses cartilage loss in aging mice and prevents the development of osteoarthritis after injuries. An oral PGDHi is already in clinical trials with the goal of treating age-related muscle loss.

Preserving muscle-building machinery

In the new study, Blau's team tested whether a PGDHi drug - by increasing prostaglandin E2 and activating muscle stem cells - could also boost muscle repair to counter the loss that occurs during GLP-1-induced weight loss.

The researchers fed young adult male mice a high-fat diet for 12 weeks to induce obesity, then treated them with semaglutide (Ozempic or Wegovy), an experimental PGDHi or both for five weeks.

Obese mice that were treated with semaglutide lost about 25% of their body weight and substantially reduced their fat levels. Semaglutide also reduced skeletal muscle mass. That muscle loss didn't translate to a loss of strength under normal conditions, but the picture changed when muscles were put under stress. The animal's muscles recovered less well after an injury.

"It wasn't just that there was an initial loss of muscle with the GLP-1 receptor agonist - it also reduced the regenerative capacity of the young mouse muscles," said Minas Nalbandian, PhD, a postdoctoral scholar in the Blau lab and first author of the new paper. "After an injury or even after routine exercise, it's very important that muscle stem cells are activated to repair and build muscle. PGDHi enhanced that regenerative response even in the setting of semaglutide-induced weight loss."

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).