Are GLP-1 weight-loss drugs hard on your muscles?
That question has sparked controversy and concern among some scientists, doctors and the general public. Several large studies in recent years had suggested that people taking GLP-1 drugs such as Zepbound or Wegovy were losing outsize proportions of their muscle mass while also shedding body fat.
In some of those studies, nearly 40 percent of people’s weight loss with GLP-1 drugs seemed to come from muscle, a much higher percentage than would be considered normal among people losing weight by dieting or other lifestyle changes.
Researchers wondered if the GLP-1 drugs might somehow be targeting muscles, causing them to shrink during weight loss, potentially contributing to weakness and sarcopenia, which is a serious decline in muscle and strength.
Those worries make the findings of a complex, multipronged new weight-loss study published in March in Cell Reports Medicine particularly intriguing. The study’s authors looked more closely than in many past experiments at changing body composition in mice receiving various types and doses of GLP-1s and also examined the drugs’ effects on strength and physical function in mice and people.
“We really wanted to learn what happens on the muscle-mass level,” said Henning Tim Langer, a principal investigator at Charité University Medicine Berlin who researches muscle wasting and aging. He was lead author of the study. “Is there a true change in muscle mass, and what happens inside of the muscle?”
The results may help ease some doubts about the effects of GLP-1s on muscles. But they also highlight the unique importance of exercise while taking the drugs and showcase how they have an outsize impact on fat embedded in the liver, which could lead to a healthier body composition overall.
More powerful GLP-1 drugs are coming
GLP-1 is an acronym for glucagon-like-peptide-1, a natural hormone created in our guts that helps regulate blood sugar and hunger. The GLP-1 drugs mimic its actions.
Early versions, such as Ozempic, focused exclusively on GLP-1. Newer and more powerful drugs, including Mounjaro (which is approved for Type 2 diabetes treatment) and Zepbound, target an additional, similar hormone, while drugs mimicking three, four or even five weight-loss pathways are in various stages of testing.
The advent of these newer drugs prompted Langer and his colleagues to mount their elaborate study, he said. Given the new formulations’ likely potency, it seemed increasingly urgent to understand how they really affect various tissues.
How much muscle do mice lose?
The scientists gathered a large group of obese mice, carefully measured the animals’ body compositions and provided them with varying versions and doses of GLP-1s. As expected, the animals lost substantial weight, most of which was body fat, but some was muscle.
Muscle loss made up barely 25 percent of the total, though, less than the 40 percent seen in some GLP-1 studies.
The main reason for this disparity, the researchers concluded, was livers. Many past GLP-1 studies in people tracked changes in body composition with scans that differentiate fat mass from lean mass and interpret loss of lean mass as, primarily, loss of muscle.
But lean mass also includes organs and, using more direct measures of tissue change, the researchers in the new study found that some organs also shrank in size during GLP-1-mediated weight loss — especially livers. They declined “massively” in weight, said Keith Baar, a physiologist at the University of California Davis School of Medicine and senior author of the study. Overall, changes in liver size represented about 20 percent of the rodents’ total weight loss.
Which was good news, Baar said. The livers had shed internal fat, making them healthier. But that shrinkage might be misinterpreted as muscle loss if researchers measure lean mass as a monolith.
Do the drugs affect strength?
The scientists also wanted to know whether GLP-1-mediated weight loss affects physical performance, in both mice and people. If losing muscle, in any amount, leads to less strength and more difficulty moving, it would contribute over time to impaired health.
But that wasn’t the case, the researchers found. After heavy mice lost weight with GLP-1s they kept pace on rodent treadmills with lean mice, even though they remained somewhat larger.
Likewise, when the researchers recruited a small group of 10 middle-aged men and women with obesity and asked them to lose weight with GLP-1s, they found that the volunteers’ leg muscles declined slightly in size but, according to leg extension testing, retained at least as much strength as before, relative to people’s body mass.
Perhaps the most unexpected study finding, though, came when the researchers placed a cast on one hind leg in obese mice and had some lose weight with the drugs. All of the animals’ immobilized leg muscles wasted, as they would in a person who sat all day, while their other back leg’s muscles grew.
But it was the effects inside the muscles’ cells that drew the scientists’ attention. In animals taking GLP-1s, they found more proteins related to improved mitochondrial function in the uncasted legs. Mitochondria are cells’ powerhouses, helping to provide energy. Healthier mitochondria mean healthier cells. So an increase in mitochondrial-related proteins signals a likely improvement in the muscle cells’ overall health, Langer said.
But that effect was seen only in the uncasted legs of mice taking GLP-1s. It didn’t appear when legs weren’t in motion or in animals not taking GLP-1s. While mice aren’t humans, that finding suggests that exercise is critically important if you’re taking a GLP-1 drug.
What the results mean
What do all of these results tell us about GLP-1s and muscles?
“First, we did see a decrease in absolute muscle mass,” in both mice and people taking the drugs, Langer said. But proportionally it was smaller than in some research “and far outpaced by how much body fat was lost.”
The muscle loss also didn’t translate into declining function, he said, so people using the drugs should be able to exercise normally.
That exercise might then amplify some of the health benefits of the drugs, Baar said, as it did in the exercised legs of mice on GLP-1s, but not their inactive legs.
“This shows just how important it is to be exercising” while using the drugs, he said. Both aerobic and resistance training would be beneficial during weight loss, he continued. “But start slowly” if you’re new to working out.
The study has limits
“This is one of the most instructive studies” completed recently, said Daniel Drucker, an endocrinologist at the University of Toronto who helped discover the actions of natural GLP-1 hormones. He was not involved with the new study. Its findings, he said, indicate that “there do not seem to be higher rates of clinical weakness or deterioration” in people or animals taking the drugs.
But questions remain. “It is a careful, important study, and one of the first to put actual function alongside muscle mass,” said Stuart Phillips, a professor of kinesiology at McMaster University in Ontario, who has studied muscle loss and aging.
But “the groups driving most of the muscle concern — such as older adults, the already sarcopenic, patients cycling on and off therapy with weight regain, and people with co-morbid wasting conditions — are precisely the ones this paper cannot speak to.”
It’s important to emphasize, too, that though the effects on muscle were similar between the rodents and people, more human studies are needed.
Langer agrees about the study’s limitations. “We don’t have much data on old people” and GLP-1s, he said. None were included in this study. Even the mice were middle-aged, in large part because weight loss can be undesirable among the elderly and frail, he said. But he and his colleagues are initiating studies of aging, GLP-1s, and the impacts on muscles and metabolic health, he said, along with other experiments focusing on the drugs’ impacts on tendons and bone.
“There’s still a lot we don’t know about the mechanisms” of the GLP-1 drugs, he said. “Stay tuned.”
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