Follistatin-315
Also known as: FS315, Follistatin short form, Circulating follistatin
Evidence: Preclinical
Overview
Mature circulating form of follistatin (315 residues), a glycoprotein that binds activin strongly and myostatin weakly; muscle-mass gains come from transgenic and gene-transfer animals, not injected protein.
Follistatin is an activin-binding glycoprotein. The FST gene makes two precursors by alternative splicing, 344 and 317 residues (Shimasaki 1988); after the signal peptide is removed these give the mature proteins FS315 and FS288. FS315 is the circulating form, with low affinity for cell-surface heparan sulfate, while the shorter FS288 sticks to cell surfaces (Sugino 1993). Follistatin binds activin A with high affinity and myostatin and GDF-11 considerably more weakly (Schneyer 2008). Transgenic mice over-expressing follistatin in muscle gained mass comparable to myostatin-knockout mice (Lee and McPherron 2001), and one AAV injection of follistatin raised muscle mass and strength in normal and dystrophic mice for over two years (Haidet 2008). No study has injected follistatin protein as a drug, in animals or humans.
Benefits
Muscle mass and strength in transgenic mice and after AAV gene transfer (rodent, >2 years of effect); activin and myostatin neutralisation in vitro. No study of injected follistatin protein in any species and no human data.
Dosing reference
- Research dose
- No dosing data in any species; research-community range 100 to 300 mcg daily in 10 to 30 day cycles
- Range
- 100 to 300 mcg, 1x daily for 10-30 days
- Reconstitution
- 1 mL bacteriostatic water
- Common vial sizes
- 1 mg
Short cycles. Very expensive. No human dosing data exists. Systemic activin blockade also suppresses FSH and affects reproductive signalling; research-grade material is frequently mislabeled or biologically inactive.
Mechanism
Follistatin binds TGF-beta superfamily ligands and blocks them from reaching activin type II receptors. Affinity is not uniform: it binds activin A tightly and myostatin (GDF-8) and GDF-11 much less so, which is why follistatin-based muscle effects come with activin-pathway effects such as FSH suppression (Schneyer 2008; Sugino 1993). FS315 is the mature secreted form with four EGF-like domains and little heparan-sulfate affinity, so it circulates rather than concentrating on cell surfaces (Shimasaki 1988; Sugino 1993). Blocking myostatin signaling through ActRIIB removes a brake on muscle growth: transgenic muscle-specific follistatin expression produced dramatic muscle-mass increases in mice, matching myostatin knockouts (Lee and McPherron 2001).
Evidence
Preclinical: animal or in vitro data only
- Transgenic mice expressing follistatin under a skeletal-muscle promoter showed muscle-mass increases comparable to myostatin-knockout mice (Lee and McPherron, 2001)
- A single AAV administration of follistatin or other myostatin inhibitors increased muscle mass and strength in normal and dystrophic mice for more than two years, including in aged animals (Haidet et al., 2008)
- Follistatin binds activin A with much higher affinity than myostatin or GDF-11, so activin-pathway effects are inseparable from the muscle effect (Schneyer et al., 2008)
- The FST gene yields 344- and 317-residue precursors by alternative splicing, giving the mature FS315 and FS288 proteins (Shimasaki et al., 1988)
- FS288, the carboxy-terminal truncated form, binds granulosa-cell heparan sulfate proteoglycans far more tightly than FS315, which is why FS315 is the circulating species (Sugino et al., 1993)
- Human-trial status: none for injected follistatin protein. The only human data are AAV1-FS344 gene-therapy trials (see Follistatin-344)
References
- Primary structure of the human follistatin precursor and its genomic organization. Shimasaki S, Koga M, Esch F, et al., Proceedings of the National Academy of Sciences, 1988
- Molecular heterogeneity of follistatin, an activin-binding protein. Higher affinity of the carboxyl-terminal truncated forms for heparan sulfate proteoglycans on the ovarian granulosa cell. Sugino K, Kurosawa N, Nakamura T, et al., Journal of Biological Chemistry, 1993
- Differential antagonism of activin, myostatin and growth and differentiation factor 11 by wild-type and mutant follistatin. Schneyer AL, Sidis Y, Gulati A, et al., Endocrinology, 2008
- Regulation of myostatin activity and muscle growth. Lee SJ, McPherron AC, Proceedings of the National Academy of Sciences, 2001
- Long-term enhancement of skeletal muscle mass and strength by single gene administration of myostatin inhibitors. Haidet AM, Rizo L, Handy C, et al., Proceedings of the National Academy of Sciences, 2008
- Myostatin inhibitor ACE-031 treatment of ambulatory boys with Duchenne muscular dystrophy: Results of a randomized, placebo-controlled clinical trial. Campbell C, McMillan HJ, Mah JK, et al., Muscle & Nerve, 2017
Side effects
No human or animal safety data exist for injected follistatin protein. Follistatin binds activin A much more tightly than myostatin (Schneyer 2008), and activin blockade affects FSH secretion and, in other drugs of this pathway, vascular integrity: ACE-031, a different activin-receptor blocker, was stopped in trials for nosebleeds and telangiectasia (Campbell 2017). Most research-grade material is E. coli-derived and may be inactive or endotoxin-bearing, which is the more immediate practical risk.
Storage
- Storage
- Refrigerate 2-8°C (36-46°F)
- Lyophilized
- 2+ years at room temp, 3+ years refrigerated
- Reconstituted
- 28-30 days refrigerated
Pharmacology
- Half-life
- Not measured for injected follistatin in any species
- Molecular weight
- 34754.3 Da