Ozempic may weaken muscles even as muscle size remains stable

A study in mice by researchers at the University of Utah Health Sciences suggests that muscle mass changes less than expected, but muscles may still get weaker, pointing out an urgent need for clinical studies to pin down the full effects of the popular medications.

"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," explained Dr Katsu Funai, associate professor of nutrition and integrative physiology in the University of Utah College of Health and the senior author on the study. "We have data in mice that suggest that things are not as straightforward as they might seem."

Researchers found that Ozempic-induced weight loss did decrease lean mass by about 10%. Most of this lost weight was not from skeletal muscles but instead from other tissues like the liver, which shrank by nearly half. The researchers emphasise that more research is needed to determine whether similar changes to organ size occur in humans and whether those changes come with any risks.

"Loss of mass in metabolically active organs, such as the liver, is expected as part of healthy weight loss," said Dr Ran Hee Choi, research instructor in nutrition and integrative physiology at U of U Health and co-first author on the study. In both mice and humans, weight gain and loss can affect the size of organs like the liver without affecting their function.

"It's unlikely that the observed lean mass loss represents a serious adverse effect," added Dr Takuya Karasawa, postdoctoral researcher in the U of U Molecular Medicine Program and co-first author on the study. Some skeletal muscles did shrink as the mice lost weight - on average, by about 6%, not enough to explain the overall loss in lean mass. Other muscles stayed the same size.

Some of this loss in muscle mass is a return to baseline, the researchers say. Gains in fat also tend to lead to gains in skeletal muscle, since the body must do more work to move around. So, loss of fat can lead to loss of muscle without affecting overall quality of life.

Interestingly, when the researchers tested the amount of force the mice's muscles could exert, they found that, for some muscles, strength decreased as the mice lost weight, even when the size of the muscle stayed roughly the same. For other muscles, strength was unchanged. It's unknown how weight loss drugs affect this balance in people, the researchers added.

A potential loss of strength when taking Ozempic may be of particular concern for adults over the age of 60, who are at higher baseline risk for muscle loss and reduced mobility.

"The loss of physical function is a strong predictor of not just quality of life but longevity," Funai added.

The researchers caution against extrapolating their results directly to humans, because mice and humans gain and lose weight in different ways. In people, obesity is associated with lower physical activity, but mice do not tend to become less active when they gain weight. And the mice in this study became overweight because they ate a high-fat diet, whereas people become overweight for a wide variety of reasons that include genetics, diet, sleeping patterns, and age. Instead of drawing a one-to-one parallel with humans, the researchers say their results emphasise the need for more clinical studies.

"There remains a significant need for validation in humans, especially concerning muscle strength," Karasawa said.

Funai stated that clinical trials should check for changes in muscle strength not just for Ozempic but also future weight-loss drugs: "There are many additional weight loss drugs that are in clinical trials and coming out in the next three to five years. But with all those clinical trials, if they're interested in measuring lean mass loss, they need to consider physical function. Our findings are really interesting, but this is a preclinical model," he adds. "We need these data in people."

The findings were reported in the paper, ‘Unexpected effects of semaglutide on skeletal muscle mass and force-generating capacity in mice’, published in Cell Metabolism. To access this paper, please click here