Females Are Completely Resistant to Semaglutide-Induced Muscle Loss in ob / ob Mice

Obesity is a major contributor to cardiometabolic disease, and pharmacological therapies, such as semaglutide, are increasingly used to induce weight loss. However, the commonly used diet-induced obesity model in C57BL/6 J mice is limited by relative resistance to weight gain in females, complicating the study of sex-specific effects. Here, we used leptin-deficient ob/ob mice, which develop severe early-onset obesity in both sexes, to investigate sex-specific responses to semaglutide on skeletal muscle mass, function, and mitochondrial metabolism. The ob/ob mice were treated daily with semaglutide or vehicle for 3 weeks, followed by assessments of body composition, muscle and organ mass, muscle contractile function, and mitochondrial efficiency. Semaglutide induced comparable reductions in body weight and food intake in both sexes but elicited distinct sex-specific changes in body composition. Consistent with previous reports, male mice exhibited relatively minor loss in skeletal muscle masses, with loss of lean mass likely coming from other lean tissues. On the other hand, female mice were completely resistant to the loss of muscle mass with semaglutide treatment. Skeletal muscle force–generating capacity remained intact in both sexes. Collectively, these findings demonstrate that mice only undergo a relatively small loss in muscle masses during pharmacologically induced weight loss, highlighting the importance of considering biological sex when evaluating the metabolic and therapeutic effects of antiobesity interventions.