Semaglutide Affects Skeletal Muscle Similarly to Caloric Restriction in Obese Mice

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.

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.

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.

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.