Follistatin 315

What it is

Follistatin 315 (FS-315) is a 315-amino acid monomeric glycoprotein derived from alternatively spliced mRNA encoding a 344-amino acid precursor (PMID 3153465; PMID 22). It functions primarily as an activin-binding protein, neutralizing activin bioactivity by forming an inactive complex (PMID 9395712; PMID 16). FS-315 differs from the FS-288 isoform by possessing an extra 27-amino acid carboxyl-terminal extension. This C-terminal extension confers low affinity for heparan sulfate proteoglycans on the cell surface, so FS-315 is predominantly secreted into circulation rather than remaining cell-associated, in contrast to FS-288 which is retained at the cell surface (PMID 8340384; PMID 9153241). Because of this difference, FS-315 has lower affinity for activin A (Kd ≈ 432 pM) compared to FS-288 (Kd ≈ 46.5 pM), and is less potent in neutralizing activin-induced transcriptional responses. In rat anterior pituitary culture, FS-315 was less potent than FS-288 in suppressing FSH release (ED50 ≈ 115–20 ng/mL vs. ≈ 9.6–2 ng/mL, respectively) (PMID 1906804; PMID 8340384). FS-315 also antagonizes myostatin (a TGF-β family member that inhibits muscle growth), and the transgene product of AAV-FS344 is a 315-amino acid peptide secreted from muscle into serum. Additionally, follistatin-315 blunts hepcidin induction during inflammation by inhibiting activin B-driven SMAD1/5/8 signaling in the liver. FS-315 has no affinity for heparan sulfate-Sepharose, does not bind to cell surfaces, and is secreted freely (PMID 8340384; PMID 9153241; PMID 9516434).

Class: Endogenous glycoprotein / activin-binding protein (TGF-β superfamily antagonist)

What it's studied for

• Muscle hypertrophy and treatment of muscle atrophy / neuromuscular disease (myostatin inhibition) Mixed
  • AAV-delivered FS344 transgene produces a 315-amino acid secreted peptide that increases muscle mass and strength in mice and monkeys without organ pathology or reproductive changes; supports gene therapy clinical trials for neuromuscular disease. PMID 19208403 Rodino-Klapac et al., Muscle & Nerve (2009)
  • Native FST315 has poor PK/PD properties for systemic therapeutic use; engineered FST315-Fc variant with heparan sulfate-binding removed showed ~100-fold improvement in half-life and ~1600-fold improvement in exposure, producing robust dose-dependent muscle effects subcutaneously in mouse models of atrophy and degenerat PMID 23249626 Datta-Mannan et al., J Pharmacol Exp Ther (2013)
  • Intramuscular AAV-FST-315 injections in young adult male mice induced muscle hypertrophy and altered adjacent bone shape (tibia anterior crest lengthening and cortical resorption adjacent to hypertrophied muscle). PMID 33869993 Chan et al., JBMR Plus (2021)
  • Follistatin expression is elevated in Mdx (Duchenne muscular dystrophy model) mice, suggesting follistatin—including its isoforms—may play a role in combating muscle loss during dystrophies. PMID 19715499 Abe et al., Zoological Science (2009)
• Liver regeneration Animal studies only
  • Intravenous FS-315 administered 72 hours after 70% partial hepatectomy in rats produced more potent stimulation of DNA synthesis and greater increase in body weight compared to controls. FS-288 was also tested. PMID 15782995 Takamura et al., Hepato-gastroenterology (2005)
  • In a CCl4-induced rat liver regeneration model, FS-315 and FS-288 mRNAs both increased beginning at 3 hours, peaked at 6 hours, and declined thereafter; FS and activin A may act reciprocally in liver regeneration. PMID 10864030 Kobayashi et al., Biol Pharm Bull (2000)
• Inhibition of hepcidin induction during inflammation (iron homeostasis) Animal studies only
  • Follistatin-315 blunted hepcidin induction by lipopolysaccharide or B. abortus in male mice, supporting a functional role for activin B in hepcidin stimulation during inflammation in vivo. PMID 26735394 Canali et al., Endocrinology (2016)
• Regulation of ovarian follicular development and FSH suppression Mixed
  • Review summarizing FS-315 and FS-288 roles in modulating ovarian biology and TGF-β superfamily members including GDF-9, BMP-15, and activin. PMID 12887271 Lin et al., Reproduction (2003)
  • Both FS-315 and FS-288 transcripts detected in human granulosa cells; three FS-315 transcripts for each FS-288 transcript; neither isoform varied significantly across follicle sizes. FS-315/288 ratio not altered in PCOS follicles. PMID 11549651 Fujiwara et al., J Clin Endocrinol Metab (2001)
  • FS-315 is the predominant mRNA in porcine follicles; FS gene expression decreased as follicles approached ovulatory status. PMID 9209088 Li et al., Biol Reprod (1997)
  • rhFS-315 expressed in CHO cells is equipotent to native porcine FS in suppressing FSH release in rat anterior pituitary culture (ED50 115.2 ± 16.2 pM). PMID 1906804 Inouye et al., Endocrinology (1991)
• Hepatic insulin sensitivity and lipid metabolism Animal studies only
  • Mice with inactivating mutation depleting the circulating FS-315 isoform (FST288-only mice) developed hepatic steatosis and elevated triglyceride content but enhanced insulin signaling, indicating activin bioavailability regulates liver lipid homeostasis and insulin response. PMID 23533219 Ungerleider et al., Endocrinology (2013)
• Pharmacokinetics of FST315-based biotherapeutics (glycosylation and clearance) Animal studies only
  • FST-ΔHBS-Fc (FS-315-based Fc fusion) is heterogeneously glycosylated at three sites in CHO cells; sialic acid content directly drives sugar-dependent clearance in mice and Cynomolgus monkeys via asialoglycoprotein receptor 1. PMID 26354950 Datta-Mannan et al., Drug Metab Dispos (2015)
• Bone repair and osteogenesis Mixed
  • FST315 loaded in alginate/recombinant collagen microspheres was mostly released over 4 weeks (unlike FST288 which was retained). Neither FST variant improved bone healing vs. control in a rat calvarial defect model. In vitro, FST promoted MSC and endothelial cell migration, tube-formation, and osteoblast mineralization PMID 30881954 Fahmy-Garcia et al., Front Bioeng Biotechnol (2019)
• Glaucoma / trabecular meshwork biology Human observational
  • FST-315 protein detected by immunohistochemistry in normal and glaucomatous human trabecular meshwork tissues. FST overall elevated in glaucomatous TM cells and tissues; TGF-β2 significantly induced FST mRNA and protein expression. PMID 23010638 Fitzgerald et al., Invest Ophthalmol Vis Sci (2012)
• Postnatal reproductive tract development (mouse model) Animal studies only
  • Female mice lacking the follistatin gene but expressing human FST-315 transgene (tghFST315) developed oviductal and uterine abnormalities (failure to coil, disorganized myometrium, reduced endometrial glands, leukocyte infiltration), demonstrating follistatin-288 is required for normal postnatal reproductive tract deve PMID 24630125 Holdsworth-Carson et al., Reprod Fertil Dev (2015)
• Early embryonic development (porcine model) Animal studies only
  • In porcine parthenogenetic embryos, 1 ng/mL FST-315 significantly increased total blastocyst cell number and trophectoderm cell number; effects differed from FST-300 and FST-288. PMID 29119699 Li et al., Anim Sci J (2018)
• Detection / anti-doping (black market product identification) Human observational
  • Of 17 black-market follistatin products tested, 9 contained His-tagged FS344 (not FS315). Some products were labeled 'follistatin 315'. Detection method: immunomagnetic purification, SDS-PAGE, Western blot with anti-His or anti-follistatin antibody. LOD in urine ~0.1 ng/mL (10 mL); LOD in serum ~5 ng/mL (100 µL). PMID 31758732 Reichel et al., Drug Test Anal (2019)

Community-reported dosing

Tier key: Research = PMID-cited study · [C] = scraped community source · [S] = model-synthesized from aggregate community reports (softer evidence). How we source.

Safety signals

• Black-market products labeled 'follistatin 315' or 'follistatin 344' frequently contain adulterants or misidentified peptides (e.g., MGF, GHRP-2, His-tagged FS344 oligomers) rather than the labeled compound, posing unknown safety risks. PMID 31758732
• Depletion of the circulating FS-315 isoform in mice (FST288-only model) caused extensive hepatic steatosis and elevated hepatic triglyceride content, despite enhanced insulin signaling, indicating disruption of liver lipid homeostasis. PMID 23533219
• Mice expressing only human FST-315 transgene (lacking FST-288) developed reproductive tract abnormalities including failure of oviductal coiling, disorganized myometrium, reduced endometrial glands, and oviductal/uterine leukocyte infiltration. PMID 24630125
• Concerns regarding potential adverse effects on the hypothalamic-pituitary-gonadal axis and reproductive capabilities were noted for follistatin use; AAV-FS344 delivered to muscle was specifically designed to avoid these off-target effects by using the secreted 315-aa peptide form. PMID 19208403
• Native FST315 has very poor pharmacokinetic properties (short half-life, low systemic exposure) when administered parenterally, suggesting that systemic effects after exogenous administration may be highly variable and difficult to predict. PMID 23249626
• Sialic acid content of FST-315-based Fc fusion proteins drives sugar-mediated clearance via asialoglycoprotein receptor 1 in mice and Cynomolgus monkeys; glycosylation heterogeneity from CHO cell expression directly impacts pharmacokinetics. PMID 26354950
• Induction of muscle hypertrophy by FST-315 (via AAV) caused adjacent cortical bone resorption and altered bone geometry in young adult male mice, suggesting potential skeletal remodeling effects. PMID 33869993

Contraindications

• No specific contraindications are stated in the reviewed literature for exogenous follistatin 315 administration in humans. Use is prohibited under WADA anti-doping rules. PMID 31758732