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 Mastaitis, Daniel R. Gomez, José G. Raya, Diana Li, Soo Min, Michael J. Stec, Sandra Kleiner, Toya McWilliams, Judith Y. Altarejos, Andrew Murphy, George D. Yancopoulos, Mark W. Sleeman
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. Myostatin and activin A are the two primary negative regulators of muscle mass. Blocking these circulating ligands during GLP-1 therapy induces improved body composition through preservation of lean mass and enhanced fat mass loss in obese primates.