Myostatin (GDF8)

Myostatin, also designated Growth Differentiation Factor 8 (GDF8), is a secreted member of the TGF-β superfamily and the principal negative regulator of skeletal muscle mass. First characterised in 1997 by McPherron, Lawler and Lee, it is produced by myofibers, circulates in a latent propeptide-bound form, and signals through activin type II receptors (ActRIIA/B) to activate SMAD2/3, suppressing satellite-cell proliferation and protein synthesis. Loss-of-function variants in cattle, dogs, and — as large-scale human genomic data confirm — multiple human carriers produce marked increases in muscle mass, establishing a causal inhibitory role. The glycoprotein follistatin neutralises myostatin by direct binding; FSTL-3 and GASP-1 provide additional extracellular regulation. Cross-sectional data show 34 % higher circulating myostatin in older versus younger women (Bergen 2015), consistent with a contribution to sarcopenia; in men the age trajectory is reversed, suggesting sex-specific homeostatic roles. A 2025 Phase I trial (Gonzalez Trotter et al.) showed that bispecific blockade of both GDF8 and activin A — but not GDF8 alone — substantially increased lean mass in postmenopausal women, indicating cooperativity between the two ligands. Several monoclonal antibodies and activin-receptor decoy ligands (bimagrumab, landogrozumab) have reached Phase II/III trials for sarcopenia and cachexia, yet none carry a specific sarcopenia approval as of 2026, and functional gains have been inconsistent across studies.