Follistatin (FST) is a glycosylated single-chain protein that is expressed in a wide variety of tissues.1 Activin stimulates pituitary FSH secretion whereas Inhibin and Follistatin are inhibitory.2 Follistatin has been shown to be a potent activin-binding protein which acts by neutralizing the actions of the Activins.3 The activin-follistatin binding complex is generally considered to be composed of one activin and two follistatin molecules, and the affinity of binding between follistatin and activin is similar to that of activin for its receptor. Several isoforms of follistatin of molecular weight 31 – 39 kDa have been identified. Molecular analysis of the isoforms indicate that follistatin is encoded by a single gene and that the variety of isoforms arise from alternative splicing, glycosylation and proteolytic cleavage. Alternative splicing occurs at the 3’-terminal of the gene resulting in a precursor form of 317 and 344 amino acids4, and then following subsequent cleavage of the 29 amino acid signal peptide, generates 2 mature follistatin isoforms of 288 and 315 amino acids (namely Follistatin-288 and Follistatin-315).
The ratio of Follistatin isoforms present in different tissues and bodily fluids varies, as does their relative binding affinities. Follistatin-288 is the predominant form present in human follicular fluid; whereas the main form in serum is Follistatin-315.5 Follistatin-288 has a greater capacity to bind and neutralize activin and is approximately 10-fold more potent than Follistatin-315 in suppressing FSH secretion from rat pituitary cells in vitro. In addition, Follistatin-288 also binds with much greater affinity to heparin sulfate proteoglycans located on the cell surface and extracellular matrix, indicating that the Follistatin-288 isoform is primarily a membrane-bound form of Follistatin, whereas Follistatin-315 is a circulating form.

References:
1. Lin SY et al. Reproduction. 126(2):133-148, 2003.
2. Robertson DM et al. Biochem Biophys Res Commun. 126(1):220-226, 1985.
3. Nakamura T et al. Science. 247(4944):836-838, 1990.
4. Shimasaki S et al. Biochem Biophys Res Commun. 152(2):717-723, 1988.
5. Schneyer AL et al. Endocrinology. 137(1):240-247, 1996.
6. HHS Publication, 5th ed., 2007. Biosafety in Microbiological and Biomedical Laboratories. Available http://www.cdc.gov/biosafety/publications/bmbl5/BMBL5
7. DHHS (NIOSH) Publication No. 78–127, August 1976. Current Intelligence Bulletin 13 – Explosive Azide Hazard. Available http:// www.cdc.gov/niosh.

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Anastasilakis AD, Polyzos SA, Rodopaios NE, Makras P, Kumar A, Kalra B, Mantzoros CS. Activins, follistatins and inhibins in postmenopausal osteoporosis: A proof of concept, case-control study. Metabolism. 2022 Dec 29:155397. doi: 10.1016/j.metabol.2022.155397. Epub ahead of print. PMID: 36587801.

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Calvert ME, Kalra B, Patel A, Kumar A, Shaw ND. Serum and urine profiles of TGF-β superfamily members in reproductive aged women. Clin Chim Acta. 2022 Jan 1;524:96-100. doi: 10.1016/j.cca.2021.12.002. Epub 2021 Dec 5. PMID: 34875272; PMCID: PMC8740174.

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deMartelly VA, Dreixler J, Tung A, Mueller A, Heimberger S, Fazal AA, Naseem H, Lang R, Kruse E, Yamat M, Granger JP, Bakrania BA, Rodriguez-Kovacs J, Rana S, Shahul S. Long-Term Postpartum Cardiac Function and Its Association With Preeclampsia. J Am Heart Assoc. 2021 Feb;10(5):e018526. doi: 10.1161/JAHA.120.018526

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Kalra B, Patel A, Kommareddy V, Ganapathy K, Mistry S, Budhavarapu V, Savjani G, Pasternack A, Ritvos O, Hyvonen M, Kumar A. Development of Novel Specific ELISAs for all Inhibins, Activins and their Binding Proteins FST and FSTL3. Poster presented at 98th Annual Endocrine Society Meeting; 2016 Apr 1-3; Boston, MA.

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Kristensen SG. Altered Levels of TGF-Beta Superfamily Growth Factors in Small Antral Follicle Fluids from Polycystic Ovaries. Poster session presented at the International Congress of Endocrinology, 2018 Dec 1-4, Cape Town South Africa.

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Legro R, Dodson W, Estes S, Kunselman A, Coutifaris C, Dokras A. Effect of Weight Loss and Hormonal Suppression Alone and in Combination on Bioactive Gut and Ovarian Peptide Hormones in Women with Polycystic Ovary Syndrome. Journal of the Endocrine Society, Volume 3, Issue Supplement_1, April-May 2019, MON-233, https://doi.org/10.1210/js.2019-MON-233

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Perakakis N, Kokkinos A, Peradze N, Tentolouris N, Ghaly W, Tsilingiris D, Alexandrou A, Mantzoros CS. Follistatins in glucose regulation of healthy and obese subjects. Diabetes Obes Metab. 2019 Mar; 21(3): 683–690

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Qi Zou, Gunnar Engström, Jingxue Pan, Jialin Zhang, Esther J. Perisho, Yanzhu Lin, Russell Wiese, Jonathan M. Wilson, Imre Pavo, Rui Gao, Kevin L. Duffin, Yang De Marinis; 741-P: Circulating Follistatin Predicts Tirzepatide Treatment Outcomes on Type 2 Diabetes. Diabetes 14 June 2024; 73 (Supplement_1): 741–P. https://doi.org/10.2337/db24-741-P

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