Follistatin exists 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 effectively neutralize activin and myostatin, resulting in clinical activities such as muscle growth and cell proliferation, with potential benefits in the treatment of cancer and diabetes.
Although Follistatin occurs naturally, a synthetic version of the full-size endogenous human protein, Follistatin-344 peptide, was developed to address deficiencies due to aging or other bodily defects.
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. Subsequent research suggested that the peptide and its synthetic version, Follistatin-344 peptide, may bind and neutralize activin and myostatin with a steady dissociation rate, 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 primarily secretes 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 effects.
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 release from blood vessels.
Research Studies on Follistatin-344 Peptide
Follistatin-344 Peptide and Cell Proliferation
According to research,(5) Follistatin may exhibit a paradoxical effect 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 Health
Myostatin is a protein that muscle cells 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 treated with Follistatin exhibited reduced myostatin levels, which improved skeletal muscle mass. These mice weighed 2 to 3 times more than their untreated counterparts, leading researchers to speculate that Follistatin may hold therapeutic potential for disorders characterized by poor muscle growth and development, such as muscular dystrophy.
In a subsequent study,(7) Follistatin was induced in mice via the nanoparticle-mediated delivery of mRNA to the liver. This mRNA messenger appeared to stimulate hepatic liver cells to synthesize and secrete Follistatin naturally. Results indicated that within 3 days of the administration, treated mice showed increased serum levels of Follistatin compared to normal mice. After 8 weeks of continuous treatment, the lean muscle mass of treated mice was 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 Treatments
Follistatin-344 peptide may have applications in cancer treatment due to its potential to regulate the activity of various proteins involved in tumorigenesis and metastasis. In breast cancer, it was observed through reverse transcription polymerase chain reaction (RT-PCR) that Follistatin levels were lower in most patients. However, some had 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, 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 treatment may counteract acid reflux, preventing the over-activation of BMP and developing esophageal cancer.(10)
Follistatin’s apparent 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 clinical applications fully, but Follistatin-344 peptide shows promising potential as a tool for cancer diagnosis and therapy.
Follistatin-344 Peptide and Liver Protection
A research study(11) was conducted to investigate the effects of Follistatin on early liver fibrosis, a condition that can lead to several chronic liver diseases. The study involved two groups of rats: one group received Follistatin treatment, while the other group served as the control. The treatment was administered for a period of four weeks. Afterward, the results reported that the group treated with Follistatin exhibited a significant decrease of 32% in liver fibrosis compared to the control group. Additionally, the Follistatin treatment appeared to decrease hepatocytic apoptosis by almost 90% in the treated mice. These findings suggest that Follistatin may be crucial in preventing liver fibrosis and protecting the liver from failure.
Follistatin-344 Peptide and Hair Growth
Recent research has indicated the potential of Follistatin in combination with other wound healing factors to stimulate interfollicular stem cells, leading to increased hair growth. In a study(12) examining the effects of a synthetic protein formulation containing Follistatin called Hair Stimulating Complex (HSC) on male pattern baldness, 26 subjects received HSC doses for 52 weeks. All subjects demonstrated good tolerance to the treatment, with no adverse events reported. Histopathological evaluation of the tissues showed improved hair growth after 52 weeks compared to placebo-treated subjects. In addition to hair growth, there was an almost 13% increase in hair thickness and density. These results suggest that Follistatin has promising potential in treating baldness and alopecia by enhancing hair growth mechanisms in males.
Follistatin-344 Peptide and Diabetes
According to a recent study,(13) Follistatin administration in diabetic mice appeared to result in 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. These findings suggest the potential of Follistatin as a therapeutic intervention for diabetic patients, improving quality of life and increasing life span. That said, further research must determine human subjects’ optimal dose levels and safety profiles.
The synthetic analog of human Follistatin, Follistatin-344 peptide, shares structural and functional similarities with its naturally occurring counterpart, operating through the activin binding pathway. Follistatin has been observed to bind and inhibit activin and other proteins belonging to the TGF-beta family.
Current research indicates that Follistatin-344 peptide holds potential in treating various types of cancer, in addition to reducing diabetes prognosis. Furthermore, researchers have reported that it may elicit muscle growth and cell proliferation, potentially increasing muscle mass. Notably, a Phase I clinical trial in men has shown the peptide’s potential to induce hair growth and treat male alopecia.
It is important to acknowledge that Follistatin-344 remains unapproved for clinical use. Ongoing trials are necessary to fully explore its effects on human subjects and establish its safety and efficacy profile in the therapeutic domain.
- 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
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Dr. Marinov (MD, Ph.D.) is a researcher and chief assistant professor in Preventative Medicine & Public Health. Prior to his professorship, Dr. Marinov practiced preventative, evidence-based medicine with an emphasis on Nutrition and Dietetics. He is widely published in international peer-reviewed scientific journals and specializes in peptide therapy research.