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One of the challenges with obesity treatments is maintaining a healthy body composition during weight loss; lean mass is reduced during weight loss (15%-40% of total weight lost) which may impact long-term durability and health benefits. Identifying an agent that safely maintains lean mass during obesity treatments could be key to sustainable, healthier weight management and improve cardiometabolic outcomes. Glucagon-like peptide-1 receptor agonists (GLP-1RAs) are effective treatments for obesity but cause considerable lean mass loss and are often discontinued due to adverse effects. Upon withdrawal, weight is regained and cardiometabolic benefits are reversed. We hypothesized that inhibiting myostatin, a negative regulator of muscle mass, during GLP-1RA-induced weight loss would maintain lean mass and result in a favorable body composition after GLP-1RA withdrawal. SRK-439 is a selective anti-pro and latent myostatin antibody that increases lean mass in mice. We tested SRK-439 in combination with the GLP-1RA semaglutide (sema) in a mouse model of diet-induced obesity (DIO). DIO mice were treated concurrently with either SRK-439 or an IgG control and sema for four weeks, sema was withdrawn, and antibody treatment was maintained for an additional four weeks. Body weight and body composition were assessed. As expected, sema treatment reduced body weight and lean mass. Animals regained their body weight two weeks after withdrawal. However, mice that received SRK-439 were protected against lean mass loss during sema treatment. Importantly, SRK-439 treatment attenuated the fat mass rebound after sema withdrawal. Mice that received sema + SRK-439 had 18.0% body fat, compared to 28.7% in the sema + IgG group (p<0.05) and circulating leptin was lower in the sema + SRK-439 group when compared to the sema + IgG group (21.7 vs 37.9 ng/mL, p<0.01). These results demonstrate that SRK-439 maintains a healthy body composition during GLP-1RA-induced weight loss. Disclosure M.A. Fulham: Employee; Scholar Rock, Inc. Stock/Shareholder; Scholar Rock, Inc. C. Chapron: Employee; Scholar Rock, Inc. F.T. Danehy: Other Relationship; Scholar Rock, Inc. F.C. Streich Jr.: Employee; Scholar Rock. Stock/Shareholder; Centessa, Cybin, Gritstone, Seres. B. Liang: Employee; Scholar Rock. Stock/Shareholder; Scholar Rock. C.J. Boston: Employee; Scholar Rock, Inc. Stock/Shareholder; Scholar Rock, Inc. J.W. Jackson: Employee; Scholar Rock, Inc. Stock/Shareholder; Scholar Rock, Inc. Y. Huang: Employee; Scholar Rock, Inc. Stock/Shareholder; Scholar Rock, Inc. S.E.B. Nicholls: Employee; Scholar Rock, Inc. Stock/Shareholder; Scholar Rock, Inc. L. Cortes: Employee; Scholar Rock. Stock/Shareholder; Scholar Rock. M. Qatanani: Employee; Scholar Rock.