1711-P: The Anti-myostatin Antibody SRK-439 Improves Grip Strength during GLP-1RA Treatment in a Mouse Model of Obesity

Introduction and Objective: Maintaining a healthy body composition during weight loss may be critical for both long-term durability and health benefits; reduced skeletal muscle mass is associated with lower basal metabolic rate, reduced strength, and overall poor health outcomes. Glucagon-like peptide-1 receptor agonists (GLP-1RAs) are effective in driving weight loss but cause significant lean mass loss. Identifying a therapy that abates lean mass loss safely may be key to healthier weight management. We hypothesized that selectively inhibiting myostatin, a negative regulator of muscle mass, during GLP-1RA-induced weight loss would preserve strength and exercise performance in a mouse model of diet-induced obesity (DIO). Methods: DIO mice were treated concurrently with either SRK-439 (a selective anti-pro/latent myostatin antibody) or an IgG control and semaglutide (sema) for five weeks. Body weight and body composition were assessed throughout the study. Fore and hindlimb grip strength were assessed on Days 0 and 21. Exercise performance was tested on Day 28. Results: As expected, sema reduced body weight and lean mass. SRK-439 increased lean mass and individual muscle weights, regardless of sema administration. Grip strength declined over time but was rescued by SRK-439 administration; IgG treated mice had a 6.4% decline in combined fore- and hindlimb grip strength compared to baseline while SRK-439-treated animals had improved grip strength from baseline by 2.3% (p<0.01). Similar results were observed in sema treated animals, with SRK-439 mitigating loss of grip strength (-8.1% (IgG) vs -3.7% (SRK-439), ns). Four weeks of SRK-439 administration did not significantly change exercise performance, but there were trends towards improved time to exhaustion and running distance. Conclusion: These results demonstrate that even short-term administration of SRK-439 can improve strength during GLP-1RA-induced weight loss. Long term studies may better assess the effects of maintaining lean mass on exercise performance. Disclosure C. Chapron: None. M.A. Fulham: Employee; Scholar Rock. Stock/Shareholder; Scholar Rock. E. Bernard: None. E. Lopez: None. L. Cortes: Employee; Scholar Rock. Stock/Shareholder; Scholar Rock. M. Qatanani: Employee; Scholar Rock.