follistatin

Follistatin, also known as activin-bindings protein, is a protein that in humans is encoded by the FST gene.{{cite journal | vauthors = Ueno N, Ling N, Ying SY, Esch F, Shimasaki S, Guillemin R | title = Isolation and partial characterization of follistatin: a single-chain Mr 35,000 monomeric protein that inhibits the release of follicle-stimulating hormone | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 84 | issue = 23 | pages = 8282–8286 | date = December 1987 | pmid = 3120188 | pmc = 299526 | doi = 10.1073/pnas.84.23.8282 | doi-access = free | bibcode = 1987PNAS...84.8282U }}{{cite journal | vauthors = Tortoriello DV, Sidis Y, Holtzman DA, Holmes WE, Schneyer AL | title = Human follistatin-related protein: a structural homologue of follistatin with nuclear localization | journal = Endocrinology | volume = 142 | issue = 8 | pages = 3426–3434 | date = August 2001 | pmid = 11459787 | doi = 10.1210/endo.142.8.8319 | doi-access = free }} Follistatin is an autocrine glycoprotein that is expressed in nearly all tissues of higher animals.

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 tissues, activin plays a significant role in cellular proliferation, while follistatin acts as safeguard against uncontrolled cellular proliferation and an instrument of cellular differentiation. These roles are vital for rebuilding and repairing tissue, and may account for the high prevalence of follistatin 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; however, endothelial cells (lining blood vessels), or macrophages and monocytes (circulating within the blood) have been proposed as likely origins, given its autocrine nature.

Follistatin acts as an inhibitor for bone morphogenic proteins (BMPs) involved in embryo development. Since BMPs facilitate the ectoderm becoming the epidermal ectoderm, their inhibition allows the ectoderm to become the neuroectoderm - eventually forming the neural plate. Other inhibitors involved in this process are noggin and chordin.

Follistatin and BMPs also participate in folliculogenesis within the ovary. The main role of follistatin is for progression of the follicle from early antral to antral/dominant in the oestrus/menstrus ovary. Follistatin is also involved in the promotion of cellular differentiation of estrogen - by converting granulosa cells (GC) to progesterone in the dominant follicle - and production of large lutein cells (LLC) in 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.{{cite journal | vauthors = Lee SJ, McPherron AC | title = Regulation of myostatin activity and muscle growth | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 98 | issue = 16 | pages = 9306–9311 | date = July 2001 | pmid = 11459935 | pmc = 55416 | doi = 10.1073/pnas.151270098 | doi-access = free | bibcode = 2001PNAS...98.9306L }}{{cite web |url=http://www.eurekalert.org/pub_releases/2007-08/jhmi-mm082407.php |title='Mighty mice' made mightier |access-date=2008-02-26 }} In 2009, research with macaque monkeys demonstrated that regulating follistatin via gene therapy also resulted in muscle growth and increases in strength.{{cite web |url=https://www.npr.org/templates/story/story.php?storyId=120316010 |title=Success Boosting Monkey Muscle Could Help Humans | work = NPR |access-date=2009-11-12| date = 11 Nov 2009 }}

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.{{cite journal | vauthors = Rose FF, Mattis VB, Rindt H, Lorson CL | title = Delivery of recombinant follistatin lessens disease severity in a mouse model of spinal muscular atrophy | journal = Human Molecular Genetics | volume = 18 | issue = 6 | pages = 997–1005 | date = March 2009 | pmid = 19074460 | pmc = 2649020 | doi = 10.1093/hmg/ddn426 }}

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.{{cite journal | vauthors = 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 | title = Elevated circulating follistatin associates with an increased risk of type 2 diabetes | journal = Nature Communications | volume = 12 | issue = 1 | pages = 6486 | date = November 2021 | pmid = 34759311 | doi = 10.1038/s41467-021-26536-w | pmc = 8580990 | bibcode = 2021NatCo..12.6486W }}{{cite journal | vauthors = Pan J, Nilsson J, Engström G, De Marinis Y | title = Elevated circulating follistatin associates with increased risk of mortality and cardiometabolic disorders | journal = Nutr Metab Cardiovasc Dis | date = 2024 | volume = 34 | issue = 2 | pages = 418–425 | doi = 10.1016/j.numecd.2023.09.012 | doi-access = free | pmid = 38000997 }}

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.{{cite journal | vauthors = Asteria C | title = Identification of follistatin as a possible trait-causing gene in polycystic ovary syndrome | journal = European Journal of Endocrinology | volume = 143 | issue = 4 | pages = 467–9 | date = October 2000 | pmid = 11022191 | doi = 10.1530/eje.0.1430467 | doi-access = free }}

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.{{cite journal | vauthors = 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 | title = Follistatin-based ligand trap ACE-083 induces localized hypertrophy of skeletal muscle with functional improvement in models of neuromuscular disease | journal = Scientific Reports | volume = 9 | issue = 1 | pages = 11392 | date = August 2019 | pmid = 31388039 | pmc = 6684588 | doi = 10.1038/s41598-019-47818-w | bibcode = 2019NatSR...911392P }}

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.{{cite journal | vauthors = Tang R, Harasymowicz NS, Wu CL, Collins KH, Choi YR, Oswald SJ, Guilak F | title = Gene therapy for follistatin mitigates systemic metabolic inflammation and post-traumatic arthritis in high-fat diet-induced obesity | journal = Science Advances | volume = 6 | issue = 19 | pages = eaaz7492 | date = May 2020 | pmid = 32426485 | pmc = 7209997 | doi = 10.1126/sciadv.aaz7492 | bibcode = 2020SciA....6.7492T }}

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

References

External links

{{MeshName|Follistatin}}
{{PDBe-KB2|P19883|Follistatin}}

Category:Proteins

Category:FOLN domain

Category:KAZAL domain

Category:Myostatin inhibitors