Follistatin

Follistatin is a glycoprotein whose main role is antagonizing the activity of transforming growth factor beta (TGF-beta) superfamily members. ^[1] It was initially characterized as a reproductive endocrine hormone that regulates follicle-stimulating hormone (FSH) secretion, and it has important counterregulatory functions in activin signaling. ^[2]

Follistatin binds activin and limits activin signaling, acting as a dynamic regulator of FSH production. ^[3] Normal maintenance of muscle mass and function depends on a dynamic balance between positive regulators of muscle growth such as follistatin and negative regulators including TGF-beta, myostatin, and activins A and B. ^[4] Myostatin, a member of the TGF-beta superfamily expressed by skeletal muscle, limits muscle growth and promotes protein breakdown, and its interaction with follistatin and other inhibitory proteins can induce a hypermuscular phenotype. ^[5] In the myostatin-activin-follistatin-inhibin system, activins and myostatin promote muscle degradation while follistatins inhibit their activity during negative energy balance, thereby preserving lean mass. ^[6]

Follistatin is one of several peptides marketed direct to patients, of which many unapproved compounds demonstrate favorable tissue-repair and metabolic outcomes in animal models while rigorous human safety data remain scarce. ^[7] A small clinical study evaluated intramuscular injection of a follistatin isoform (FS344) delivered by AAV1 combined with exercise in patients with inclusion body myositis, with improvement in physical capacity associated with higher exercise levels. ^[8] Exercise training modulates growth factors including IGF-1, myostatin, and follistatin, changes that support muscle anabolism and reduce catabolic signaling. ^[9] An ESCEO expert consensus recommended the Myostatin-Follistatin pair among the biochemical markers of musculoskeletal status to be assessed in Phase II or Phase III clinical trials of drugs for sarcopenia. ^[10]

Follistatin is a candidate biomarker for sarcopenia, the age-related decline in skeletal muscle mass and function that heavily burdens the health care system as life expectancy increases. ^[4] The activin-follistatin system is being explored to preserve muscle and bone during the substantial weight loss produced by incretin receptor agonists, over 25% of which typically comes from fat-free mass including skeletal muscle. ^[6] With reproductive aging, follistatin does not appear to change greatly in men or women, whereas circulating activin increases and inhibin B declines. ^[2]