Role of Activin Type II Receptor Signaling in Muscle Hypertrophy, Obesity, and Weight Loss

Project Summary GLP-1 receptor agonists and GLP-1/GIP dual agonists profoundly decrease body weight in association with significant cardiometabolic benefits. These therapeutic agents are being widely adopted for obesity treatment in the U.S. Certainly, lowering fat mass is metabolically advantageous; however, reduction of lean mass, especially skeletal muscle mass, is associated with poor health outcomes including reduced energy expenditure that could contribute to weight regain and functional defects in certain patient populations. Lean mass loss during GLP-1 receptor agonism is as great or greater than dieting or bariatric surgery. Discontinuing therapy leads to rapid weight regain, favoring increased adiposity and limited muscle growth. Thus, a major goal of next generation anti-obesity agents should be to maximize quality weight loss by reducing fat mass while preserving (even increasing) lean muscle mass. Myostatin and other TGF-b-like ligands, such as activins, are potent negative regulators of skeletal muscle mass acting primarily via the activin type II receptors (ActRII). Blockade of ActRII in both rodents and humans drives increased muscle mass that is associated with reductions in adipose tissue. The holy grail for an obesity treatment is an approach that maximizes reductions in fat mass while sparing lean tissues such as skeletal muscle. Excitingly, recent published and preliminary data in this application show that bimagrumab co-treatment in animals receiving semaglutide (a GLP-1 agonist) leads to even greater reductions fat mass while preserving functional lean mass in mice. These findings indicate that ActRII blockade protects against muscle loss and drive increased fat loss during calorie deficit, potentially leading to more durable and sustained metabolic benefits and diminishing susceptibility to “rebound” weight gain. In Aim 1 of this proposal, the effects of ActRII on systemic energy balance and metabolism both during and following the cessation of GLP-1/GIP receptor agonism will be explored. In Aim 2, the tissue specific mechanisms of ActRII blockade in the control of muscle and adipose tissue physiology will be elucidated. Collectively the experiments in this proposal will address critical knowledge gaps regarding how ActRII blockade alters muscle, adipose tissue and whole-body energy metabolism when given as a mono-therapy or in combination with GLP-1/GIP receptor agonists laying the foundation for future therapeutic opportunities targeting body composition for enhanced weight loss quality in obesity.