- Follistatin, by Jawahar Swaminathan and MSD staff at the European Bioinformatics Institute via Wikimedia Commons

Follistatin 344 (or FS-344) acts as a precursor to the protein follistatin when administered to animals as a laboratory-grade peptide. Mature follistatin regulates the release of follicle-stimulating hormone (FSH) through the inhibition of activin¹. Naturally, activin (also known as activin-A) is classically viewed as an FSH-level promoter, although it may have other roles in accordance to the part of the body in which it is present. Therefore, FS-344 may be present in any tissue that also contains activin (according to some studies on rats). These include skeletal muscle, several vital organs, the thymus and part of the cerebral cortex, although the majority of follistatin molecules may be found in the gonads and anterior pituitary². Follistatin also has other targets in vivo, the best-studied of which are myostatin and growth differentiation factor-11 (GDF-11)¹. This may be due to the close homogeneity in structure between activin and these additional proteins³. Myostatin and GDF-11 were also perceived as similar in function at one time, although more up-to-date research indicates that they have wildly different roles in mammalian systems³. Myostatin is associated with muscle development after birth, whereas GDF-11 has more diverse functions in development³. This suggests a diverse range of future applications for follistatin and for derivatives such as FS-344.

There are a number of applications for FS-344 in the laboratory and in animal studies. These may mostly concern experiments on the roles of activin in various tissues, due to the influence of follistatin on this protein. FS-344 is composed of all the amino acids that can comprise the protein, whereas species-specific isoforms are spliced or further processed into slightly smaller variants (e.g. FS-315)⁴. The presence of FS-344 mRNA was originally confirmed in porcine studies⁵. It has also been found in rats, and stood out at the time as the most abundant messenger RNA associated with follistatin precursors (of which there are indeed others, e.g. FS-317) in this animal². FS-344 also distinguishes itself through a novel 27-amino acid tail at the C-terminus, which other smaller follistatin precursors lack⁵. Follistatin derivatives have also recently attracted attention as research agents in murine models of muscle growth and development^1,6. This is due to the inhibitory effects of the protein on myostatin, which has a role in the negative regulation of cardiac and skeletal muscle mass³.

Some groups have also reported results suggesting roles for follistatin and/or its derivatives in inflammatory processes, scar tissue formation, hair growth and tissue re-modeling^4,7,8. The anti-inflammatory effects of follistatin are most likely to be due to its binding of activin, which has been shown to be released in response to animal models of immune-system challenge⁸. Follistatin may also reduce mortality in these animals, due to the neutralization of activin and, thus, increased inflammation⁸. However, activin may also promote tissue re-modeling. Therefore, follistatin may be used to selectively modulate tissue regeneration, leading to the improved control of wound healing and fibrosis in animals affected by disorders of the relevant processes⁸. Few formal studies have been conducted to elucidate the pharmacokinetics or pharmacodynamics of FS-344. However, a study of the same of the splice-variant FS-315 suggests that follistatin exhibits rapid clearance and limited distribution⁴. Therefore, local (e.g. intramuscular for muscle mass and/or regeneration studies) as opposed to systemic administration may be advisable when incorporating FS-344 into a study.

References:

1. Yaden BC, Croy JE, Wang Y, et al. Follistatin: a novel therapeutic for the improvement of muscle regeneration. J Pharmacol Exp Ther. 2014;349(2):355-371.
2. Michel U, Albiston A, Findlay JK. Rat follistatin: gonadal and extragonadal expression and evidence for alternative splicing. Biochem Biophys Res Commun. 1990;173(1):401-407.
3. Walker RG, Poggioli T, Katsimpardi L, et al. Biochemistry and Biology of GDF11 and Myostatin: Similarities, Differences, and Questions for Future Investigation. Circulation research. 2016;118(7):1125-1142.
4. Datta-Mannan A, Yaden B, Krishnan V, Jones BE, Croy JE. An engineered human follistatin variant: insights into the pharmacokinetic and pharmocodynamic relationships of a novel molecule with broad therapeutic potential. J Pharmacol Exp Ther. 2013;344(3):616-623.
5. Shimasaki S, Koga M, Esch F, et al. Porcine follistatin gene structure supports two forms of mature follistatin produced by alternative splicing. Biochem Biophys Res Commun. 1988;152(2):717-723.
6. Tsuchida K. Myostatin inhibition by a follistatin-derived peptide ameliorates the pathophysiology of muscular dystrophy model mice. Acta Myol. 2008;27:14-18.
7. Fumagalli M, Musso T, Vermi W, et al. Imbalance between activin A and follistatin drives postburn hypertrophic scar formation in human skin. Experimental dermatology. 2007;16(7):600-610.
8. de Kretser DM, O'Hehir RE, Hardy CL, Hedger MP. The roles of activin A and its binding protein, follistatin, in inflammation and tissue repair. Molecular and cellular endocrinology. 2012;359(1-2):101-106.