Follistatin (FST), a naturally occurring glycoprotein, is considered to be present in various tissues. Classified as an autocrine factor,(1) scientists consider that the endogenous protein stimulates the production of a chemical messenger by the cell itself, which binds to the autocrine receptors of the same cell, resulting in cellular modifications.
Follistatin appears to exist in two isoforms, FST-317 and FST-344, composed of 317 and 344 amino acids, respectively, due to the alternative splicing process of mRNA.(2) Follistatin-344 is available for research purposes and will be the primary subject of this article. Initially considered to inhibit follicle-stimulating hormone (FSH), Follistatin research has suggested it may potentially neutralize activin and myostatin, resulting in activities such as muscle cell proliferation and fiberous tissue development.
In 1987, Follistatin was initially discovered following its isolation from bovine and porcine follicular fluid,(3) which was thought to inhibit the follicle-stimulating hormone solely. Although Follistatin occurs naturally, a synthetic version of the full-size endogenous protein, Follistatin-344 peptide, was developed. Subsequent research suggested that both the endogenous peptide and its synthetic version, Follistatin-344, may bind and neutralize activin and myostatin with a steady dissociation rate, potentially resulting in nearly irreversible binding.
How does the Follistatin-344 Peptide Work?
Follistatin-344 appears to exert its biological activity by binding to activin.(4) It appears to be collaborative in reproductive functioning alongside other molecules, including activin and inhibins. The ovarian follicle is considered to primarily secrete activin, enhancing the secretion of follicle-stimulating hormone (FSH). Assuming its binding activity, Follistatin-344 peptide may thereby attenuate the secretion of FSH and reduce its impact.
While the origin and mechanism of Follistatin remain incompletely understood, it is assumed that the peptide hormone is produced locally in the pituitary gland, gonads (i.e., testes and ovaries), and various organs throughout the body. Follistatin appears widely distributed in the bloodstream due to its apparent release from blood vessels.
Follistatin-344 Peptide and Cell Proliferation
According to research,(5) Follistatin may exhibit a paradoxical actioin on cellular function, inhibiting metastasis while promoting cell proliferation. This peculiar duality may explain why this peptide is linked to increased tumor growth (tumorigenesis) and is associated with reduced invasion and spread of tumors (metastasis).
Specifically, one study found that hepatocytes, or liver cells, appear to require Follistatin to proliferate. In experimental rats, it was suggested that the inactivation of activin by Follistatin is a necessary precondition for cell proliferation. There may be an energetic trade-off between cell migration and growth/proliferation, whereby the energy required for cell migration is suppressed in favor of cellular growth and proliferation.
Follistatin-344 Peptide and Muscle Function
Myostatin is a protein that muscle cells appear to synthesize to inhibit muscle cell differentiation and growth. As a transforming growth factor-beta (TGF-beta) protein family member, Follistatin-344 peptide likely regulates myostatin.
In a 1997 study,(6) mice exposed to Follistatin exhibited reduced myostatin levels, which improved skeletal muscle mass. These mice weighed 2 to 3 times more than their unexposed counterparts, leading researchers to speculate that Follistatin may hold potential for research in disorders characterized by poor muscle growth and development, such as muscular dystrophy.
In a subsequent study,(7) Follistatin was introduced via the nanoparticle-mediated delivery of mRNA to the liver of the mice model. This mRNA messenger appeared to stimulate hepatic liver cells to synthesize and secrete Follistatin naturally. Results indicated that within 3 days of the exposure, the Follistatin mice appeared to exhibit increased serum levels of Follistatin compared to control mice. After 8 weeks of continuous exposure, the lean muscle mass of exposed mice appeared 10% greater than that of control mice. As per Schumann C et al., “Based on the obtained results demonstrating an increased muscle mass as well as restricted fat accumulation, this might be a milestone in the development of mRNA technologies and the treatment of muscle wasting disorders.”
Follistatin-344 Peptide and Cancer Cells
Follistatin-344 peptide has been examined within the context of cancer cell research, due to its potential to regulate the activity of various proteins involved in tumorigenesis and metastasis. In breast cancer studies, it was observed through reverse transcription polymerase chain reaction (RT-PCR) that Follistatin levels appeared lower in most cases. However, some exhibited reportedly higher levels associated with fast-growing but less invasive tumor cells.(8)
In a mouse breast cancer model, Follistatin appeared to be under-expressed in carcinogenic cells, possibly leading to increased spread of cancer cells via activin proteins. Restoration of Follistatin was suggested to inhibit activin-induced metastasis and improve overall survival. Studies suggest “these data indicate that FST is a bona fide metastasis suppressor in this mouse model and support future efforts to develop an FST mimetic to suppress metastatic progression.” (9)
Similarly, bone morphogenic protein (BMP) has been identified as a causative factor in developing cancerous tissue in esophageal cancer. Follistatin-344 peptide exposure may potentially counteract acid reflux, possibly preventing the over-activation of BMP and developing esophageal cancer development.(10)
Follistatin’s possible antagonistic function on TGF-beta proteins, including activin and BMPs, suggests its potential role in tumorigenesis, angiogenesis, and metastasis of cancerous tumors. Further research is needed to explore its expression of action fully, but Follistatin-344 peptide shows promising potential within the realm of cancer research.
Follistatin-344 Peptide and the Liver
A research study(11) was conducted to investigate the impact of Follistatin in research models of early liver fibrosis, a condition that may lead to chronic liver diseases. The study involved two groups of rats: one group received Follistatin, while the other group served as the control. The Follistatin was introduced for a period of four weeks. Afterward, the results reported that the group with Follistatin exhibited a significant decrease of 32% in liver fibrosis compared to the control group. Additionally, the Follistatin exposure appeared to decrease hepatocytic apoptosis by almost 90% in the exposed mice. These findings suggest that Follistatin may be impactful within the context of liver fibrosis.
Follistatin-344 Peptide and Hair Follicle Development
Recent research has indicated the potential of Follistatin to stimulate interfollicular stem cells, leading to increased hair follicle growth. In a study(12) examining the impact of a synthetic protein formulation containing Follistatin called Hair Stimulating Complex (HSC), 26 research models underwent exposure to HSC for 52 weeks. Histopathological evaluation of the tissues reported an uptick in hair growth after 52 weeks compared to placebo models. In addition to follicle growth, there was a reported ~13% increase in hair thickness and density.
Follistatin-344 Peptide and Diabetes
According to a recent study,(13) Follistatin exposure in mice models of diabetes appeared to lead to the overexpression of the protein in pancreatic cells. This overexpression led to increased pancreatic beta cell mass, decreased glucose levels, and an overall reduction in diabetic symptoms. Research is ongoing.
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- Hiroyuki Kaneko, Handbook of Hormones, 2016. https://www.sciencedirect.com/topics/neuroscience/follistatin
- FST follistatin [Homo sapiens (human)]. https://www.ncbi.nlm.nih.gov/gene?Db=gene&Cmd=DetailsSearch&Term=10468
- Shi, L., Resaul, J., Owen, S., Ye, L., & Jiang, W. G. (2016). Clinical and Therapeutic Implications of Follistatin in Solid Tumours. Cancer genomics & proteomics, 13(6), 425–435. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5219916/
- Rodino-Klapac, L. R., Haidet, A. M., Kota, J., Handy, C., Kaspar, B. K., & Mendell, J. R. (2009). Inhibition of myostatin with emphasis on follistatin as a therapy for muscle disease. Muscle & nerve, 39(3), 283–296. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2717722/
- Ooe H, Chen Q, Kon J, Sasaki K, Miyoshi H, Ichinohe N, Tanimizu N, Mitaka T. Proliferation of rat small hepatocytes requires follistatin expression. J Cell Physiol. 2012 Jun;227(6):2363-70. https://pubmed.ncbi.nlm.nih.gov/21826650/
- McPherron AC, Lawler AM, Lee SJ. Regulation of skeletal muscle mass in mice by a new TGF-beta superfamily member. Nature. 1997 May 1;387(6628):83-90. https://pubmed.ncbi.nlm.nih.gov/9139826/
- Schumann C, Nguyen DX, Norgard M, Bortnyak Y, Korzun T, Chan S, Lorenz AS, Moses AS, Albarqi HA, Wong L, Michaelis K, Zhu X, Alani AWG, Taratula OR, Krasnow S, Marks DL, Taratula O. Increasing lean muscle mass in mice via nanoparticle-mediated hepatic delivery of follistatin mRNA. Theranostics 2018; 8(19):5276-5288. doi:10.7150/thno.27847. https://www.thno.org/v08p5276.htm
- Zabkiewicz C, Resaul J, Hargest R, Jiang WG, Ye L. Increased Expression of Follistatin in Breast Cancer Reduces Invasiveness and Clinically Correlates with Better Survival. Cancer Genomics Proteomics. 2017 Jul-Aug;14(4):241-251. https://pubmed.ncbi.nlm.nih.gov/28647698/
- Seachrist DD, Sizemore ST, Johnson E, Abdul-Karim FW, Weber Bonk KL, Keri RA. Follistatin is a metastasis suppressor in a mouse model of HER2-positive breast cancer. Breast Cancer Res. 2017 Jun 5;19(1):66. https://pubmed.ncbi.nlm.nih.gov/28583174/
- Lau MC, Ng KY, Wong TL, Tong M, Lee TK, Ming XY, Law S, Lee NP, Cheung AL, Qin YR, Chan KW, Ning W, Guan XY, Ma S. FSTL1 Promotes Metastasis and Chemoresistance in Esophageal Squamous Cell Carcinoma through NFκB-BMP Signaling Cross-talk. Cancer Res. 2017 Nov 1. https://pubmed.ncbi.nlm.nih.gov/28883005/
- Patella S, Phillips DJ, Tchongue J, de Kretser DM, Sievert W. Follistatin attenuates early liver fibrosis: effects on hepatic stellate cell activation and hepatocyte apoptosis. Am J Physiol Gastrointest Liver Physiol. 2006 Jan;290(1):G137-44. https://pubmed.ncbi.nlm.nih.gov/16123203/
- Zimber MP, Ziering C, Zeigler F, Hubka M, Mansbridge JN, Baumgartner M, Hubka K, Kellar R, Perez-Meza D, Sadick N, Naughton GK. Hair regrowth following a Wnt- and follistatin containing treatment: safety and efficacy in a first-in-man phase 1 clinical trial. J Drugs Dermatol. 2011 Nov;10(11):1308-12. https://pubmed.ncbi.nlm.nih.gov/22052313/
- Zhao C, Qiao C, Tang RH, Jiang J, Li J, Martin CB, Bulaklak K, Li J, Wang DW, Xiao X. Overcoming Insulin Insufficiency by Forced Follistatin Expression in β-cells of db/db Mice. Mol Ther. 2015 May;23(5):866-874. doi: 10.1038/mt.2015.29. Epub 2015 Feb 13. PMID: 25676679; PMCID: PMC4427879. https://pubmed.ncbi.nlm.nih.gov/25676679/
- Image credit: Image source: UniProtKB – P19883 (FST_HUMAN). https://www.uniprot.org/uniprot/P19883