Follistatin

Mechanism (as reported)

A study of an N-terminal domain (ND) of follistatin reported that ND-derived fragment peptides were identified that inhibit myostatin while failing to inhibit activin A or TGF-β1 in an in vitro reporter assay, supporting a selective myostatin inhibitory interaction based on the follistatin ND interacting with a myostatin receptor binding site. (PMID 31874826) Reviews describe follistatin as antagonizing TGF-β superfamily members through binding to activin, neutralizing activin effects. (PMID 9799587; PMID 10077456; PMID 34087433)

Key findings (each cites a source)

• A research study reported that N-terminal domain (ND) fragments of follistatin can be used to identify a new myostatin inhibitory 14-mer peptide (DF-3) that inhibited myostatin but failed to inhibit activin A or TGF-β1 in an in vitro luciferase reporter assay. [PMID 31874826]
• The same study reported that DF-3 increased skeletal muscle mass in mice after intramuscular injection and described DF-3 as a platform for development of muscle enhancement based on myostatin inhibition. [PMID 31874826]
• A structure–activity relationship study reported that modifying DF-3 to address oxidation susceptibility (substituting a methionine residue) and introducing additional amino-acid substitutions produced a derivative (DF-100) with about twice the potent inhibitory ability as DF-3. [PMID 34087433]
• A study reported that follistatin-derived peptide expression in muscle decreased adipose tissue mass and prevented hepatic steatosis, with findings in FS I-I transgenic mice including smaller adipocytes, resistance to high-fat diet-induced obesity, lower hepatic fatty acid levels, altered fatty acid composition, and improved glucose tolerance when placed on a high-fat diet. [PMID 21205933]
• A pulmonary arterial hypertension study reported measuring serum levels of activin A, activin B, inhibin subunits, and antagonists including follistatin and follistatin-like 3 (FSTL3), and reported that activin A and FSTL3 were associated with transplant-free survival with prognostic values supported by an external validation cohort. [PMID 37096577]
• The same PAH study reported histological findings of phosphorylated Smad2/3 accumulation and altered immunoreactivity patterns for multiple activin pathway components, while reporting lower immunostaining for inhibin-α and follistatin in PAH vascular layers. [PMID 37096577]
• A review article described follistatin as a multifunctional regulatory protein whose effects are facilitated through affinity for activin, neutralizing activin effects via binding. [PMID 9799587]
• A review article on activin/follistatin and atherosclerosis described an activin-A/follistatin system in relation to atherosclerotic lesion development, including discussion of activin-A downregulation of MSR and follistatin-upregulated MSR expression in the context of foam cell formation. [PMID 10077456]
• A review on metabolic disorders reported that connections between follistatin (and follistatin-like 3) and metabolic disorders such as type 2 diabetes, obesity, and gestational diabetes have been investigated, but noted contradictory outcomes and the need for further research to clarify their exact roles. [PMID 37739334]
• A narrative review reported that investigations of healthy subjects suggested the liver contributes significantly to circulating follistatin levels and that circulating follistatin is tightly regulated by the glucagon-to-insulin ratio. [PMID 27264073]