Aging exacerbates muscle loss induced by semaglutide treatment in female mice

Abstract

Background Glucagon-like peptide-1 receptor agonists (GLP-1RAs), including semaglutide, have transformed the pharmacological treatment of obesity. While highly efficacious in promoting weight loss, these drugs also induce substantial reductions in lean mass, raising concerns for skeletal muscle loss, particularly in older individuals vulnerable to sarcopenia. Nevertheless, there are currently no published human studies that investigated the effects of GLP-1RAs on skeletal muscle mass using gold standard methods. Meanwhile, studies in young mice demonstrate that skeletal muscle loss induced by GLP-1RAs might not be a major concern. The purpose of the current study was to investigate the effects of semaglutide on skeletal muscle mass and strength in aged mice. Methods Eighteen-month-old male and female C57BL/6J mice were fed a high-fat diet (HFD) for 12 weeks to induce obesity. At 21 months of age, mice received daily subcutaneous injections of vehicle or semaglutide (3 or 30 nmol/kg) for 3 weeks. Body composition was assessed weekly by nuclear magnetic resonance (NMR) spectroscopy. After 3 wks, mice were terminated to assess masses of individual organs including skeletal muscle. Skeletal muscle force-generating capacity was assessed by ex vivo electrical stimulation-induced contraction. Myofiber cross-sectional area and fiber-type composition were also assessed. Results Semaglutide induced dose-dependent weight loss in both sexes, with reductions of 11.3% and 20.2% in males and 21.1% and 26.1% in females receiving 3 or 30 nmol/kg dose, respectively. There was a substantial sex-difference in the loss of lean mass, with relatively minor reductions in males (2.3% and 6.6%) and greater loss in females (8.6% and 8.3%). Skeletal muscle mass was largely preserved in males but females exhibited greater muscle mass loss, including 14.2% reduction in quadriceps mass at 30 nmol/kg of semaglutide treatment. In contrast, skeletal muscle force-generating capacity was not compromised in semaglutide-treated females, while males exhibited 19.2% reduction in force generating capacity of the extensor digitorum longus (EDL) muscles at the 30 nmol/kg dose. Conclusion Unlike young mice, semaglutide treatment may induce meaningful loss in skeletal muscle mass in aged female mice and muscle strength in aged male mice. These findings highlight the importance of considering age as a potential factor that may negatively influence muscle mass and function in humans treated with GLP-1RAs. Clinical studies examining the influence of pharmacological weight loss on skeletal muscle mass and strength should consider both age and sex as a potentially important determinant of these outcomes.