Semaglutide reduced muscle size and strength to the same degree as matched caloric restriction in obese mice, but was more effective at promoting fat loss, and muscle recovered after treatment stopped.
Muscle loss equal between groupsSemaglutide reduced muscle size and strength to the same extent as caloric restriction alone, suggesting the effect is driven by energy deficit, not the drug itself.
What the researchers found
Semaglutide produced greater total weight loss than caloric restriction alone, even when calorie intake was matched between groups. Both treatments reduced muscle mass and strength to a similar extent, indicating that semaglutide's effect on muscle is primarily driven by reduced energy intake rather than a direct drug effect on muscle tissue.
Importantly, transcriptomic analyses of skeletal muscle revealed distinct molecular responses between semaglutide-treated and calorie-restricted mice, suggesting the drug does have unique effects at the gene expression level despite similar functional outcomes.
After discontinuation, both lean mass and fat mass rebounded to baseline levels within six weeks, and muscle size and strength were comparable across all groups at the end of the withdrawal period.
Why it matters
A major concern with GLP-1 drugs like semaglutide is that patients lose muscle along with fat, potentially harming metabolic health and physical function. This study provides reassuring evidence that semaglutide's muscle impact is no worse than what happens with ordinary dieting, and that muscle recovers after stopping treatment. However, the rebound in both fat and lean mass after discontinuation also underscores the challenge of maintaining weight loss without ongoing treatment.
How the study worked
Mice were first made obese through a high-fat diet, then divided into groups receiving either semaglutide injections or a calorie-matched restricted diet for four weeks. Researchers measured body weight, body composition (lean and fat mass), energy expenditure, muscle size, grip strength, and performed gene expression analysis (transcriptomics) on skeletal muscle. In a follow-up experiment, treatments were stopped after four weeks and the mice were monitored for six additional weeks to track weight and body composition rebound.
What this study cannot tell us
This study was conducted in mice, and results may not directly translate to humans. The four-week treatment period is relatively short. Calorie matching was done at the group level, which may not perfectly replicate individual variation. The study did not assess long-term outcomes beyond the six-week withdrawal period, and did not test whether exercise or protein supplementation could mitigate muscle loss.
How to read the evidence
This is a preclinical animal study using a controlled experimental design with calorie-matched comparisons and a follow-up withdrawal experiment. While well-designed for a mouse study, animal results require human confirmation before clinical conclusions can be drawn.
When this study was published
Published in 2025, this study addresses a highly current question about the body composition effects of GLP-1 receptor agonists during the peak of clinical adoption of these drugs.
The bigger picture
As GLP-1 receptor agonists like semaglutide and tirzepatide become mainstream obesity treatments, understanding their effects on lean tissue is critical. This preclinical study adds to growing evidence that semaglutide-related muscle loss mirrors what occurs with any caloric deficit, which may help clinicians counsel patients about expected body composition changes. The rebound findings also highlight why researchers are exploring combination therapies that could help maintain weight loss after GLP-1 discontinuation.
Questions still open
- Do the distinct transcriptomic changes in muscle from semaglutide versus caloric restriction lead to meaningful functional differences over longer treatment periods?
- Could resistance exercise or increased protein intake during semaglutide treatment prevent the muscle loss seen in this study?
- What strategies might prevent the rebound weight gain observed after semaglutide discontinuation?
Common questions
Does semaglutide cause more muscle loss than regular dieting?
Does muscle come back after stopping semaglutide?
Read the original research
Semaglutide impacts skeletal muscle to a similar extent as caloric restriction in mice with diet-induced obesity.
The Journal of physiology
Citation
Jeromson, S; Baranowski, B; Akcan, M; Waters, B D; Eisner, K; Bellucci, A; Trang, S; Abolhassani, A; Tello-Palencia, M A; Schweitzer, A; Stefanska, B; Mitchell, C J; Wright, David C. (2025). Semaglutide impacts skeletal muscle to a similar extent as caloric restriction in mice with diet-induced obesity.. The Journal of physiology. https://doi.org/10.1113/JP289449