Targeting activin/myostatin-ActRII pathway offers strategy to preserve muscle mass in obesity

The rise of effective anti-obesity treatments, including GLP-1R agonists and bariatric surgery, has revolutionized weight management, but often results in significant loss of lean body mass, including skeletal muscle. This muscle loss can lead to sarcopenia, worsening metabolic health and functional decline, especially in sarcopenic obesity. The activin/myostatin-ActRII pathway is a critical negative regulator of muscle growth, making it a promising target to counteract muscle wasting during weight loss.

This comprehensive review synthesizes current literature on the activin/myostatin-ActRII pathway's role in skeletal muscle mass regulation, particularly in the context of obesity and weight loss. Researchers explored the mechanistic insights linking this pathway to muscle atrophy and evaluated emerging therapeutic strategies. The analysis focused on preclinical and early clinical data concerning various ActRII antagonists and their potential to mitigate sarcopenia associated with significant weight reduction.

The review highlights that obesity and rapid weight loss, including that induced by GLP-1R agonists, often lead to significant loss of lean body mass, exacerbating sarcopenia. It details how myostatin and activin A, members of the TGF-β superfamily, bind to ActRIIB receptors, activating downstream Smad2/3 signaling to inhibit muscle protein synthesis and promote degradation. These mechanisms contribute to the observed muscle atrophy. The review also discusses how ActRII signaling can impact mitochondrial function and inflammation in skeletal muscle. Potential therapeutic strategies include ActRIIB soluble receptors, anti-myostatin antibodies, and follistatin, a natural TGF-β antagonist. These interventions have shown promise in preclinical models by increasing muscle mass and strength. The review emphasizes that targeting this pathway could offer a way to decouple fat loss from muscle loss. It also notes that ActRIIB antagonists can improve metabolic parameters beyond just muscle mass, such as insulin sensitivity. The authors underscore the importance of understanding the precise molecular mechanisms to develop targeted and effective therapies. They also discuss the interplay between ActRII signaling and other pathways involved in muscle homeostasis, such as mTORC1 and AMPK.