GLP-1 receptor agonists have transformed obesity and diabetes care by helping millions shed excess weight—but new mouse research suggests the popular drug may also subtly sap muscle strength, even when muscle size appears unchanged.
The study titled, “Unexpected effects of semaglutide on skeletal muscle mass and force-generating capacity in mice,” published in Cell Metabolism, suggests that semaglutide, a popular GLP-1 receptor agonist, may have unexpected effects on skeletal muscle function that warrant further investigation in humans.
Researchers at the University of Utah Health set out to explore how semaglutide affects lean mass and muscle strength in a controlled mouse model of diet-induced obesity. Previous studies have shown that GLP-1 receptor agonists like semaglutide can reduce body weight—including lean body mass—but the specifics of which tissues are affected, and how, remain unclear.
According to the study, “Male C57BL/6J mice were fed with high-fat diet (HFD) for 12 weeks, after which they were treated with daily injections of vehicle or semaglutide for one or three weeks for the assessment of hindlimb muscle mass and force-generating capacity.” Additionally, the HFD-mice were treated with a clinically relevant dose of 3 nmol/kg of semaglutide.
The researchers also report that from another recent study, two-week daily injections of 120 µg/kg (30 nmol/kg) of semaglutide in mice induced ~10% loss of lean mass accompanied by equivalent reduction in hindlimb muscle mass. The researchers added that, “while the study nicely highlighted the influence of semaglutide on reducing individual muscle mass, semaglutide dose was much higher than what is generally prescribed to people.”
“Loss of mass in metabolically active organs, such as the liver, is expected as part of healthy weight loss,” explained Ran Hee Choi, PhD, a co-first author on the study. Interestingly, the skeletal muscle changes were relatively modest. Some muscles shrank slightly—by about 6% on average—while others stayed the same size. But when researchers tested muscle strength, they noticed something surprising: even muscles that maintained their size were sometimes weaker.
This decoupling of size and function raises red flags, especially for older adults. “The loss of physical function is a strong predictor of not just quality of life but longevity,” said senior author Katsu Funai, PhD. “We have data in mice that suggest that things are not as straightforward as they might seem.
“If we want to really help the individuals who may be losing muscle mass, then we need to know that they’re actually losing muscle mass,” added Funai. The team emphasized that their findings cannot be directly applied to humans. Mice and people gain and lose weight differently, and obesity affects human behavior and activity levels in ways it doesn’t in lab mice. Still, the results underscore the need for clinical trials that go beyond measuring lean mass.
“There remains a significant need for validation in humans, especially concerning muscle strength,” said co-first author Takuya Karasawa, PhD. Funai agreed, adding, “With all those clinical trials, if they’re interested in measuring lean mass loss, they need to consider physical function too.”
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