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<p>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.</p>

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

  • 期刊论文

  • 出版模式：

    开放获取

  • 发表日期：

    2025年5月13日

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  • 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,
  • Mark W. Sleeman

摘要

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.