Targeting the activin/myostatin - actrii pathway to preserve skeletal muscle mass in obesity: mechanistic insights and therapeutic perspectives

Skeletal muscle deterioration is a relevant complication of obesity associated with poor physical function, impairment of metabolic homeostasis, and worse lifelong outcomes. The phenomenon can be accentuated by weight loss, especially in patients with poor skeletal muscle health at baseline (e.g., sarcopenic obesity) and those experiencing rapid and significant slimming. Preserving and even strengthening skeletal muscle mass during weight loss would be a novel therapeutic target, as disproportionate fat to skeletal muscle mass loss reduces metabolic rate, physical performance, and long-term health benefits. Anti-obesity pharmacotherapies, especially glucagon-like peptide 1 receptor agonists and tirzepatide, preferentially reduce fat mass while partially sparing skeletal muscle, though significant lean mass loss has been described in individuals with pronounced weight reduction. The review aims to elucidate innovatively the mechanistic role of the activin/myostatin receptor pathways in obesity-associated skeletal muscle atrophy and explore therapeutic strategies targeting this axis to preserve muscle mass, quality, and function. Targeted inhibition of the activin/myostatin pathway is a novel strategy to enhance muscle trophism. Activin receptor (IIA/IIB) blockade prevents the small mothers against decapentaplegic homolog 2/3-mediated muscle catabolism, promoting myofibrillar synthesis, myoblast differentiation, and hypertrophy. Bimagrumab - a human anti-activin receptor antibody - consistently increases skeletal muscle mass and improves body composition across populations, including sarcopenic adults, patients with disuse atrophy, and individuals with obesity. While gains in strength are variable, this approach represents a promising adjunct to lifestyle and pharmacologic interventions. Integrating skeletal muscle preservation into obesity management may optimize functional, metabolic, and clinical outcomes, representing a paradigm shift in comprehensive care.