PD1027 - GLP-1 MEDICINES FOR WEIGHT LOSS DO NOT CAUSE DISPROPORTIONATE MUSCLE LOSS IN VIVO OR IMPAIR MUSCLE PROTEIN SYNTHESIS IN VITRO

PD1027

GLP-1 MEDICINES FOR WEIGHT LOSS DO NOT CAUSE DISPROPORTIONATE MUSCLE LOSS IN VIVO OR IMPAIR MUSCLE PROTEIN SYNTHESIS IN VITRO

A. S. Joshi^1,*, H. T. Langer¹, N. Haritonow ¹, U. Müller-Werdan¹, N. K. Gilmore², C. M. T. Hayden², A. Roos^3,4, A. Hentschel⁵, K. Norman^1,6, K. Baar^2,7

¹Department of Geriatrics and Medical Gerontology, Charité-Universitätsmedizin Berlin, Berlin, Germany, ²Department of Neurobiology, Physiology and Behavior, University of California, Davis, Davis, CA, United States, ³Department of Neuropediatrics and Neuromuscular Centre for Children and Adolescents, University Hospital Essen, Duisburg-Essen University, Essen, Germany, ⁴Brain and Mind Research Institute, Children’s Hospital of Eastern Ontario Research Institute, Ottawa, Canada, ⁵Leibniz-Institut für Analytische Wissenschaften-ISAS-e.V., Dortmund, ⁶Department of Nutrition and Gerontology, German Institute of Human Nutrition Potsdam Rehbrücke, Nuthetal, Germany, ⁷Department of Physiology and Membrane Biology, University of California, Davis Health, Davis, CA, United States

Rationale: Glucagon-like peptide-1 (GLP-1) medicines lead to substantial reductions in body weight, prompting concerns of loss in lean body mass (LBM) and skeletal muscle.

Methods: Using mouse models and a proof-of-concept clinical trial, we assessed the effect of GLP-1 medicines on skeletal muscle mass and strength in middle-aged mice and individuals with obesity. Muscle protein synthesis was evaluated in immortalized or primary muscle cells treated with varying doses of different GLP-1 medicines. To examine effects on muscle atrophy, a cast-induced immobilization model was employed, followed by proteomic analysis to identify protein-level alterations.

Results: Our study demonstrates that GLP-1 medicines predominantly reduce fat mass but also lead to a modest but significant reduction in LBM. While absolute muscle mass and strength were reduced in response to GLP-1 medicines, there was a significant improvement in relative muscle mass and strength and running performance in adult mice. Interestingly, GLP-1 medicines did not exacerbate immobilization-induced muscle atrophy in adult mice but produced a distinct muscle proteome compared to calorie-restriction alone. Consistent with the in vivo findings, GLP-1 medicines had minimal effects on protein synthesis rates and signaling in cultured muscle cells at pharmacologically relevant concentrations. Furthermore, results from a proof-of-concept clinical trial revealed that obese individuals receiving GLP-1 treatment showed improved body composition without any adverse effect on muscle strength.

Conclusion: The findings of this study indicate that weight loss with GLP-1 medicines does not result in excessive muscle loss or alteration in muscle protein synthesis. Rather, GLP-1 medicines positively impact body composition and mobility in middle-aged mice or individuals with obesity.

Disclosure of Interest: A. S. Joshi: None declared, H. Langer Consultant for: Worked as a consultant for Actimed Therapeutics, Almac Discovery, Alchemab Therapeutics, and Novartis. None of these engagements are related to this work., Other: Previously employed by Boehringer Ingelheim (2023–2024), N. Haritonow : None declared, U. Müller-Werdan: None declared, N. Gilmore: None declared, C. Hayden: None declared, A. Roos: None declared, A. Hentschel: None declared, K. Norman: None declared, K. Baar Consultant for: Worked as a consultant for food companies such as PepsiCo, Ynsect, Advanced Muscle Technologies, GelTor, Evergrain, and Digestiva, Other: Co-founder of SinewUS, a tendon loading company