Activin and myostatin-related transforming growth factor-beta superfamily ligands (Activin/Myostatin ligands)

Activin and myostatin-related ligands are a subset of the transforming growth factor-beta (TGF-beta) superfamily that serve as critical extracellular regulators of tissue growth and homeostasis [3, 10]. This group includes Myostatin (GDF-8), Activin A, Activin B, and Growth Differentiation Factor 11 (GDF-11), which primarily signal through the activin type II receptors (ActRIIA and ActRIIB) to activate the Smad2/3 intracellular pathway [1, 7]. Myostatin and Activin A are well-characterized negative regulators of skeletal muscle mass, while GDF-11 and activins are implicated in the inhibition of late-stage erythroid maturation and the promotion of pathological vascular remodeling [15, 20]. In diseases such as pulmonary arterial hypertension (PAH), an imbalance between these proliferative ligands and antiproliferative bone morphogenetic protein (BMP) signaling leads to vessel narrowing [6, 14]. Therapeutic interventions include ligand traps like sotatercept and luspatercept, which are fusion proteins that sequester these ligands to restore physiological balance [2, 9]. Additionally, monoclonal antibodies targeting specific ligands or their activation processes are being investigated for muscle-wasting conditions, obesity, and neuromuscular disorders [11, 13]. By inhibiting these "brakes" on tissue growth and maturation, these therapies aim to increase muscle mass, improve red blood cell production, and reverse vascular remodeling [17, 22].

Other names

Activin AActivin BMyostatinGDF-8GDF-11Growth differentiation factor 8Growth differentiation factor 11TGF-beta superfamily ligandsActRII ligands

Drugs targeting these ligands primarily act as ligand traps or monoclonal antibodies [4, 11]. Ligand traps, such as sotatercept and luspatercept, are recombinant fusion proteins consisting of the extracellular domain of activin receptors (ActRIIA or ActRIIB) linked to an Fc domain; these molecules sequester circulating ligands like activins, myostatin, and GDF-11, preventing them from binding to cell-surface receptors [2, 19]. Monoclonal antibodies may directly neutralize specific ligands (e.g., garetosmab for Activin A) or selectively inhibit the proteolytic activation of latent complexes (e.g., apitegromab for pro-myostatin) [7, 13]. These actions reduce downstream Smad2/3 signaling, thereby alleviating the inhibitory effects on muscle growth, erythroid maturation, and vascular homeostasis [15, 26].