Follistatin Explained

Follistatin, also known as activin-bindings protein, is a protein that in humans is encoded by the FST gene.^{[1] [2]} Follistatin is an autocrine glycoprotein that is expressed in nearly all tissues of higher animals.^[2]

Its primary function is the binding and bioneutralization of members of the TGF-β superfamily, with a particular focus on activin, a paracrine hormone.

An earlier name for the same protein was FSH-suppressing protein (FSP). At the time of its initial isolation from follicular fluid, it was found to inhibit the anterior pituitary's secretion of follicle-stimulating hormone (FSH).

Biochemistry

Follistatin is part of the inhibin-activin-follistatin axis.

Three isoforms, FS-288, FS-300, and FS-315 have been reported. Two, FS-288 and FS-315, are created by alternative splicing of the primary mRNA transcript. FS-300 (porcine follistatin) is thought to be the product of posttranslational modification via truncation of the C-terminal domain from the primary amino-acid chain.

Although FS is ubiquitous, its highest concentration is in the female ovary, followed by the skin.

Follistatin is produced by folliculostellate (FS) cells of the anterior pituitary. FS cells make numerous contacts with the classical endocrine cells of the anterior pituitary including gonadotrophs.

Function

In the tissues activin has a strong role in cellular proliferation, thereby making follistatin the safeguard against uncontrolled cellular proliferation and also allowing it to function as an instrument of cellular differentiation. These roles are vital in tissue rebuilding and repair, and may account for follistatin's high presence in the skin.

In the blood, activin and follistatin are involved in the inflammatory response following tissue injury or pathogenic incursion. The source of follistatin in circulating blood plasma has yet to be determined, but due to its autocrine nature speculation suggests the endothelial cells lining all blood vessels, or the macrophages and monocytes circulating within the whole blood, may be sources.

Follistatin is involved in embryo development. It has inhibitory action on bone morphogenic proteins (BMPs); BMPs induce the ectoderm to become epidermal ectoderm. Inhibition of BMPs allows neuroectoderm to arise from ectoderm, a process which eventually forms the neural plate. Other inhibitors involved in this process are noggin and chordin.

Follistatin and BMPs are play a role in folliculogenesis within the ovary. The main role of follistatin in the oestrus/menstrus ovary appears to be progression of the follicle from early antral to antral/dominant. It is also involved in the promotion of cellular differentiation of the estrogen producing granulosa cells (GC) of the dominant follicle into the progesterone producing large lutein cells (LLC) of the corpus luteum.

Clinical significance

Follistatin is studied for its role in regulation of muscle growth in mice, as an antagonist to myostatin (also known as GDF-8, a TGF superfamily member) which inhibits excessive muscle growth. Lee and McPherron demonstrated that inhibition of GDF-8, either by genetic elimination (knockout mice) or by increasing the amount of follistatin, resulted in increased muscle mass.^{[3] [4]} In 2009, research with macaque monkeys demonstrated that regulating follistatin via gene therapy also resulted in muscle growth and increases in strength.^[5]

Increased levels of follistatin, by leading to increased muscle mass of certain core muscular groups, can increase life expectancy in cases of spinal muscular atrophy (SMA) in animal models.^[6]

Elevated circulating follistatin levels are also associated with increased risk of type 2 diabetes, early death, heart failure, stroke and chronic kidney disease. It has been demonstrated that follistatin contributes to insulin resistance in type 2 diabetes development and nonalcoholic fatty liver disease (NAFLD). The genetic regulation of follistatin secretion from the liver is via Glucokinase regulatory protein (GCKR) identified by large GWAS studies. ^{[7] [8]}

It is also investigated for its involvement in polycystic ovary syndrome (PCOS), in part to resolve debate as to its direct role in this disease.^[9]

Sporadic inclusion body myositis, a variant of inflammatory myopathy, involves muscle weakness. In one clinical trial, rAAV1.CMV.huFS344, 6 × 1011 vg/kg, walk test results significantly improved versus untreated controls, along with decreased fibrosis and improved regeneration.

ACE-083, a follistatin-based fusion protein, was investigated for treatment focal or asymmetric myopathies. Intramuscular ACE-083 increased growth and force production in injected muscle in wild-type mice and mouse models of Charcot-Marie-Tooth disease (CMT) and Duchenne muscular dystrophy, without systemic effects or endocrine disruption.^[10]

AAV-mediated FST reduced obesity-induced inflammatory adipokines and cytokines systemically and in synovial fluid. Mice receiving FST therapy were protected from post-traumatic osteoarthritis and bone remodeling from joint injury.^[11]

In another mouse study, high dose animals showed significant quadricep growth.

Further reading

• Thompson TB, Lerch TF, Cook RW, Woodruff TK, Jardetzky TS . The structure of the follistatin:activin complex reveals antagonism of both type I and type II receptor binding . Developmental Cell . 9 . 4 . 535–543 . October 2005 . 16198295 . 10.1016/j.devcel.2005.09.008 . free .
• Nakatani M, Takehara Y, Sugino H, Matsumoto M, Hashimoto O, Hasegawa Y, Murakami T, Uezumi A, Takeda S, Noji S, Sunada Y, Tsuchida K . Transgenic expression of a myostatin inhibitor derived from follistatin increases skeletal muscle mass and ameliorates dystrophic pathology in mdx mice . FASEB Journal . 22 . 2 . 477–487 . February 2008 . 17893249 . 10.1096/fj.07-8673com . free . 10405000 .
• Lambert-Messerlian G, Eklund E, Pinar H, Tantravahi U, Schneyer AL . Activin subunit and receptor expression in normal and cleft human fetal palate tissues . Pediatric and Developmental Pathology . 10 . 6 . 436–445 . 2007 . 18001154 . 10.2350/06-05-0087.1 . 13268973 .
• Walsh S, Metter EJ, Ferrucci L, Roth SM . Activin-type II receptor B (ACVR2B) and follistatin haplotype associations with muscle mass and strength in humans . Journal of Applied Physiology . 102 . 6 . 2142–2148 . June 2007 . 17347381 . 2646094 . 10.1152/japplphysiol.01322.2006 .
• Ogino H, Yano S, Kakiuchi S, Muguruma H, Ikuta K, Hanibuchi M, Uehara H, Tsuchida K, Sugino H, Sone S . Follistatin suppresses the production of experimental multiple-organ metastasis by small cell lung cancer cells in natural killer cell-depleted SCID mice . Clinical Cancer Research . 14 . 3 . 660–667 . February 2008 . 18245525 . 10.1158/1078-0432.CCR-07-1221 . free .
• Reis FM, Nascimento LL, Tsigkou A, Ferreira MC, Luisi S, Petraglia F . Activin A and follistatin in menstrual blood: low concentrations in women with dysfunctional uterine bleeding . Reproductive Sciences . 14 . 4 . 383–389 . May 2007 . 17644811 . 10.1177/1933719107303985 . 28945135 .
• Yerges LM, Klei L, Cauley JA, Roeder K, Kammerer CM, Moffett SP, Ensrud KE, Nestlerode CS, Marshall LM, Hoffman AR, Lewis C, Lang TF, Barrett-Connor E, Ferrell RE, Orwoll ES, Zmuda JM . High-density association study of 383 candidate genes for volumetric BMD at the femoral neck and lumbar spine among older men . Journal of Bone and Mineral Research . 24 . 12 . 2039–2049 . December 2009 . 19453261 . 2791518 . 10.1359/jbmr.090524 .
• Blount AL, Vaughan JM, Vale WW, Bilezikjian LM . A Smad-binding element in intron 1 participates in activin-dependent regulation of the follistatin gene . The Journal of Biological Chemistry . 283 . 11 . 7016–7026 . March 2008 . 18184649 . 10.1074/jbc.M709502200 . free .
• Eichberger T, Kaser A, Pixner C, Schmid C, Klingler S, Winklmayr M, Hauser-Kronberger C, Aberger F, Frischauf AM . GLI2-specific transcriptional activation of the bone morphogenetic protein/activin antagonist follistatin in human epidermal cells . The Journal of Biological Chemistry . 283 . 18 . 12426–12437 . May 2008 . 18319260 . 2430996 . 10.1074/jbc.M707117200 . free .
• Jones MR, Wilson SG, Mullin BH, Mead R, Watts GF, Stuckey BG . Polymorphism of the follistatin gene in polycystic ovary syndrome . Molecular Human Reproduction . 13 . 4 . 237–241 . April 2007 . 17284512 . 10.1093/molehr/gal120 . free .
• Torres PB, Florio P, Ferreira MC, Torricelli M, Reis FM, Petraglia F . Deranged expression of follistatin and follistatin-like protein in women with ovarian endometriosis . Fertility and Sterility . 88 . 1 . 200–205 . July 2007 . 17296189 . 10.1016/j.fertnstert.2006.11.105 . free .
• Sidis Y, Mukherjee A, Keutmann H, Delbaere A, Sadatsuki M, Schneyer A . Biological activity of follistatin isoforms and follistatin-like-3 is dependent on differential cell surface binding and specificity for activin, myostatin, and bone morphogenetic proteins . Endocrinology . 147 . 7 . 3586–3597 . July 2006 . 16627583 . 10.1210/en.2006-0089 . free .
• Grusch M, Drucker C, Peter-Vörösmarty B, Erlach N, Lackner A, Losert A, Macheiner D, Schneider WJ, Hermann M, Groome NP, Parzefall W, Berger W, Grasl-Kraupp B, Schulte-Hermann R . Deregulation of the activin/follistatin system in hepatocarcinogenesis . Journal of Hepatology . 45 . 5 . 673–680 . November 2006 . 16935389 . 10.1016/j.jhep.2006.06.014 .
• Chen M, Sinha M, Luxon BA, Bresnick AR, O'Connor KL . Integrin alpha6beta4 controls the expression of genes associated with cell motility, invasion, and metastasis, including S100A4/metastasin . The Journal of Biological Chemistry . 284 . 3 . 1484–1494 . January 2009 . 19011242 . 2615501 . 10.1074/jbc.M803997200 . free .
• Blount AL, Schmidt K, Justice NJ, Vale WW, Fischer WH, Bilezikjian LM . FoxL2 and Smad3 coordinately regulate follistatin gene transcription . The Journal of Biological Chemistry . 284 . 12 . 7631–7645 . March 2009 . 19106105 . 2658057 . 10.1074/jbc.M806676200 . free .
• Phillips DJ, de Kretser DM . Follistatin: a multifunctional regulatory protein . Frontiers in Neuroendocrinology . 19 . 4 . 287–322 . October 1998 . 9799587 . 10.1006/frne.1998.0169 . 3023421 .
• Chang SY, Kang HY, Lan KC, Hseh CY, Huang FJ, Huang KE . Expression of inhibin-activin subunits, follistatin and smads in granulosa-luteal cells collected at oocyte retrieval . Journal of Assisted Reproduction and Genetics . 23 . 9–10 . 385–392 . 2006 . 17053951 . 3455100 . 10.1007/s10815-006-9068-7 .
• Kostek MA, Angelopoulos TJ, Clarkson PM, Gordon PM, Moyna NM, Visich PS, Zoeller RF, Price TB, Seip RL, Thompson PD, Devaney JM, Gordish-Dressman H, Hoffman EP, Pescatello LS . Myostatin and follistatin polymorphisms interact with muscle phenotypes and ethnicity . Medicine and Science in Sports and Exercise . 41 . 5 . 1063–1071 . May 2009 . 19346981 . 4147954 . 10.1249/MSS.0b013e3181930337 .
• Flanagan JN, Linder K, Mejhert N, Dungner E, Wahlen K, Decaunes P, Rydén M, Björklund P, Arver S, Bhasin S, Bouloumie A, Arner P, Dahlman I . Role of follistatin in promoting adipogenesis in women . The Journal of Clinical Endocrinology and Metabolism . 94 . 8 . 3003–3009 . August 2009 . 19470636 . 3214594 . 10.1210/jc.2008-2005 .
• Peng C, Ohno T, Khorasheh S, Leung PC . Activin and follistatin as local regulators in the human ovary . Biological Signals . 5 . 2 . 81–89 . 1996 . 8836491 . 10.1159/000109177 .

Notes and References

1. Ueno N, Ling N, Ying SY, Esch F, Shimasaki S, Guillemin R . Isolation and partial characterization of follistatin: a single-chain Mr 35,000 monomeric protein that inhibits the release of follicle-stimulating hormone . Proceedings of the National Academy of Sciences of the United States of America . 84 . 23 . 8282–8286 . December 1987 . 3120188 . 299526 . 10.1073/pnas.84.23.8282 . free . 1987PNAS...84.8282U .
2. Tortoriello DV, Sidis Y, Holtzman DA, Holmes WE, Schneyer AL . Human follistatin-related protein: a structural homologue of follistatin with nuclear localization . Endocrinology . 142 . 8 . 3426–3434 . August 2001 . 11459787 . 10.1210/endo.142.8.8319 . free .
3. Lee SJ, McPherron AC . Regulation of myostatin activity and muscle growth . Proceedings of the National Academy of Sciences of the United States of America . 98 . 16 . 9306–9311 . July 2001 . 11459935 . 55416 . 10.1073/pnas.151270098 . free . 2001PNAS...98.9306L .
4. Web site: 'Mighty mice' made mightier . 2008-02-26 .
5. Web site: Success Boosting Monkey Muscle Could Help Humans . NPR . 2009-11-12. 11 Nov 2009 .
6. Rose FF, Mattis VB, Rindt H, Lorson CL . Delivery of recombinant follistatin lessens disease severity in a mouse model of spinal muscular atrophy . Human Molecular Genetics . 18 . 6 . 997–1005 . March 2009 . 19074460 . 2649020 . 10.1093/hmg/ddn426 .
7. Wu C, Borné Y, Gao R, López Rodriguez M, Roell WC, Wilson JM, Regmi A, Luan C, Aly DM, Peter A, Machann J, Staiger H, Fritsche A, Birkenfeld AL, Tao R, Wagner R, Canouil M, Hong MG, Schwenk JM, Ahlqvist E, Kaikkonen MU, Nilsson P, Shore AC, Khan F, Natali A, Melander O, Orho-Melander M, Nilsson J, Häring HU, Renström E, Wollheim CB, Engström G, Weng J, Pearson ER, Franks PW, White MF, Duffin KL, Vaag AA, Laakso M, Stefan N, Groop L, De Marinis Y . Elevated circulating follistatin associates with an increased risk of type 2 diabetes . Nature Communications . 12 . 1 . 6486 . November 2021 . 34759311 . 10.1038/s41467-021-26536-w . 8580990 . 2021NatCo..12.6486W .
8. Pan J, Nilsson J, Engström G, De Marinis Y . Elevated circulating follistatin associates with increased risk of mortality and cardiometabolic disorders . Nutr Metab Cardiovasc Dis . 2024 . 34 . 2 . 418–425 . 10.1016/j.numecd.2023.09.012 . free . 38000997 .
9. Asteria C . Identification of follistatin as a possible trait-causing gene in polycystic ovary syndrome . European Journal of Endocrinology . 143 . 4 . 467–9 . October 2000 . 11022191 . 10.1530/eje.0.1430467 . free .
10. Pearsall RS, Davies MV, Cannell M, Li J, Widrick J, Mulivor AW, Wallner S, Troy ME, Spaits M, Liharska K, Sako D, Castonguay R, Keates S, Grinberg AV, Suragani RN, Kumar R . Follistatin-based ligand trap ACE-083 induces localized hypertrophy of skeletal muscle with functional improvement in models of neuromuscular disease . Scientific Reports . 9 . 1 . 11392 . August 2019 . 31388039 . 6684588 . 10.1038/s41598-019-47818-w . 2019NatSR...911392P .
11. Tang R, Harasymowicz NS, Wu CL, Collins KH, Choi YR, Oswald SJ, Guilak F . Gene therapy for follistatin mitigates systemic metabolic inflammation and post-traumatic arthritis in high-fat diet-induced obesity . Science Advances . 6 . 19 . eaaz7492 . May 2020 . 32426485 . 7209997 . 10.1126/sciadv.aaz7492 . 2020SciA....6.7492T .