GDF8 and activin A blockade protects against GLP-1–induced muscle loss while enhancing fat loss in obese male mice and non-human primates

Jason W. Mastaitis, Daniel Gomez, José G. Raya, Diana Li, Soo Min, Michael Stec, Sandra Kleiner, Toya McWilliams, Judith Y. Altarejos, Andrew J. Murphy, George D. Yancopoulos and Mark W. Sleeman ()
Additional contact information
Jason W. Mastaitis: Regeneron Pharmaceuticals
Daniel Gomez: Regeneron Pharmaceuticals
José G. Raya: Regeneron Pharmaceuticals
Diana Li: Regeneron Pharmaceuticals
Soo Min: Regeneron Pharmaceuticals
Michael Stec: Regeneron Pharmaceuticals
Sandra Kleiner: Regeneron Pharmaceuticals
Toya McWilliams: Regeneron Pharmaceuticals
Judith Y. Altarejos: Regeneron Pharmaceuticals
Andrew J. Murphy: Regeneron Pharmaceuticals
George D. Yancopoulos: Regeneron Pharmaceuticals
Mark W. Sleeman: Regeneron Pharmaceuticals

Nature Communications, 2025, vol. 16, issue 1, 1-8

Abstract: Abstract Glucagon-like peptide-1 receptor agonists act via appetite suppression and caloric restriction. These treatments can result in significant muscle loss, likely due to evolutionary mechanisms protecting against food scarcity as muscle is a major energy utilizer. One mechanism that reduces muscle mass involves activation of type II activin receptors, ActRIIA/B, which yield profound muscle growth in humans when blocked. We previously demonstrated GDF8, also known as myostatin, and activin A are the two major ActRIIA/B ligands mediating muscle minimization. Here, we report that dual blockade can also prevent muscle loss associated with glucagon-like peptide-1 receptor agonists – and even increase muscle mass – in both obese mice and non-human primates; moreover, this muscle preservation enhances fat loss and is metabolically beneficial. These data raise the possibility that supplementing glucagon-like peptide-1 receptor agonist treatment with GDF8 and activin A blockade could greatly improve the quality of weight loss during the treatment of obesity in humans.

Date: 2025
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DOI: 10.1038/s41467-025-59485-9

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