Follistatin-344 is a naturally occurring glycoprotein that is present in almost all tissues in the body. This is an autocrine chemical, meaning that the cell, through a form of cell signal, produces a chemical messenger, which binds to its autocrine receptors, resulting in cell modification.(1)
Follistatin is naturally available in two isoforms, FST 317 and FST 344, each composed of 317 and 344 amino acids, respectively. These two isoforms are produced due to the alternative splicing process of the mRNA.(2)
At the time of initial discovery and isolation, Follistatin-344 was believed to primarily inhibit the secretion of gonadal hormone follicle-stimulating hormone (FSH). However, with comprehensive research, it has been established that this human protein has efficient neutralizing effects on activin and myostatin as well. These effects result in clinical activities, including muscle growth, and cell proliferation, with potential benefits in treating cancer and diabetes.
While Follistatin-344 is naturally formed in the body, a synthetic version of the protein is also available to combat any Follistatin deficiencies pertaining to increased age or other bodily defects.
Introduction to the Follistatin-344 Peptide
Follistatin-344 is a synthetic version of the endogenous Follistatin-344 human protein isoform.
Although the number of amino acids differs in Follistatin isoforms, at its core, the human protein is composed of 63 amino acid residues along with three domains: FSD1, FSD2, and FSD3. The same applies to the synthetic peptide.(3)
Follistatin-344 was first discovered in 1987, upon isolation from the bovine and porcine follicular fluid, where the primary function of the protein was believed to be solely limited to the inhibition of follicle-stimulating hormone.(1,3)
Later, it was established that the peptide could bind and neutralize activin and myostatin, and this binding is almost irreversible due to its steady dissociation rate.
Role of Follistatin-344 Peptides
Follistatin-344 is mainly able to exert its effect due to its ability to bind with activin.(4) Follistatin has a collaborative role in reproductive functioning along with other chemicals such as activin and inhibins. The ovarian follicle mainly releases activin to enhance the secretion of follicle-stimulating hormone. Follistatin binds with activin and thereby attenuates its effect by inhibiting the secretion of the FSH hormone in the body.
While the origin and mechanism of the peptide hormone are not entirely understood, it has been established that Follistatin-344 is locally produced in the pituitary gland, gonads, testes, and ovaries. Additionally, Follistatin is vastly distributed in various organs of the body and is also found in blood circulation due to its secretion from the blood vessels.
Clinical Significance of Follistatin-344 Peptides
The various benefits of Follistatin-344 peptides include:
- Improved muscle growth
- Enhanced cell proliferation
- Increased lean muscle mass
- Liver protection
- Ability to induce hair growth
- Ability to combat insulin deficiency
- Role in inhibiting congenital blindness
- Potential therapeutic agent to treat muscle disorders, including myositis and muscle dystrophy
- Potential agent to combat breast cancer and esophageal cancer
Research and Clinical Studies
Muscle Development and Growth
Myostatin is a protein synthesized by the muscle cells, hindering muscle cell differentiation and growth. Myostatin protein belongs to the transforming growth factor-beta (TGF-beta) protein which Follistatin inhibits.
During one 1997 study,(5) it was noted that mice treated with Follistatin-344had reduced levels of myostatin, which helped improve skeletal muscle mass with each mouse weighing 2 to 3 times more than usual. This led the scientists to believe that Follistatin could be helpful in treating disorders such as muscular dystrophy, characterized by poor muscle growth and development.
In another study,(6) Follistatin-344 was induced in mice via a nanoparticle-mediated mode of delivery of mRNA in the liver through subcutaneous administration. This mRNA messenger stimulated the hepatic liver cells to synthesize and secrete Follistatin naturally. Results of this study showed that the treated mice, administered with this mRNA-containing nanoparticle, showed increased serum levels of Follistatin within 3 days of administration as compared to the levels in normal mice. After 8 weeks of continuous treatment, the lean muscle mass of the treated mice was 10% more than the control mice.
Role in Improving Muscular Dystrophy
In another study,(7) mice with induced Duchenne muscular dystrophy (also called the MDX model) were treated with synthetic Follistatin-344 for 12 weeks. After the treatment, it was seen that there was a dose-dependent increment in lean muscle mass in the MDX mice. Additionally, there was improved grip strength and increased muscle markers for inflammation and fibrosis levels. There was a prominent improvement in the muscle dystrophy pathway, which positively indicates the therapeutic abilities of the peptide.
Follistatin-344 has proven capabilities of improving muscle mass and development in various animal models, which can also be helpful in human disease management.
Role in Cancer Treatment
It was noted, through reverse transcription polymerase chain reaction study (RT-PCR), that Follistatin levels fluctuated in breast cancer patients. While most of the patients had lower levels of Follistatin-344, a handful of patients had higher levels. Patients with high levels had fast-growing, but less invasive tumor cells.(8)
One study(9) examined the available gene expression data of mice suffering from breast cancer. In most cases, Follistatin was under-expressed in carcinogenic breast cells, leading to the increased spread of cancer cells caused by activin proteins. As Follistatin is known to bind to and inhibit activin proteins, it was found that restoring Follistatin in these mice would prevent the prognosis of activin-induced metastasis and improve overall survival.
Research indicates that bone morphogenic protein (BMP) is one of the causative factors in the transition of normal esophageal tissue to cancerous tissues. Treatment with Follistatin-344 helps counteract acid reflux, thereby preventing the over-activation of BMP and the development of esophageal cancer.(10)
Because of its antagonistic function on the TGF-beta proteins, such as activin and BMP, Follistatin-344 is believed to play a significant role in tumorigenesis, angiogenesis, and metastasis of cancerous tumors. It can therefore play an effective role in cancer diagnosis and therapy.11 While more research is needed to explore its clinical applications fully, Follistatin shows promising potential for use in cancer treatment.
Role in Cell Proliferation
There is an odd contrast in the working of Follistatin, where it inhibits metastasis but promotes cell proliferation. This is why the peptide is associated with increased tumor growth (tumorigenesis) but also linked with reduced invasion and spread of tumors (metastasis).(12)
Research has shown that hepatocytes (i.e., liver cells) require Follistatin to proliferate. When studied in experimental rats, it was seen that the inactivation of activin by Follistatin-344 is a precondition for cell proliferation to occur. It is believed that there may be some energy exchange amongst the cells where the energy used for cell migration is shut off to switch with cellular growth and proliferation.
Role in Liver Protection
One study(14) was conducted to determine the effects of Follistatin on early liver fibrosis, which is the precursor to several chronic liver ailments.
In this study, rats were divided into one control group and one Follistatin-treated group for a period of four weeks. The treatment group showed a 32% decrease in liver fibrosis as compared to the control group. The hepatocytic apoptosis was decreased by almost 90% in the Follistatin-treated mice.
This suggests that Follistatin-344 plays a significant role in preventing liver fibrosis, thereby protecting the organ from failure.
Role in Improved Hair Growth
Follistatin peptide wound healing factors stimulate interfollicular stem cells, which lead to increased hair growth. A study was conducted where the effects of this synthetic protein formulation, termed Hair Stimulating Complex (HSC), were studied in subjects with male pattern baldness.(14)
26 candidates were treated with HSC injections for a period of 52 weeks. All 26 candidates showed sound tolerance towards this application with no reported adverse events. Histopathological evaluation of the tissues showed improved hair growth after 52 weeks as compared to the placebo-treated subjects. Besides hair growth, there was also an improvement in hair thickness and density by almost 13%.
This suggests that Follistatin plays a promising role in combating baldness and alopecia by inducing improved hair growth mechanisms in males.
Role in Diabetes Management
Diabetes is one of the most common ailments, leading to chronic complications and sometimes even death. While it is known to be mainly caused by insulin resistance and insufficiency, very few medications are available that preserve pancreatic beta cell functions while overcoming this insulin insufficiency.
Research has shown that when Follistatin-344 was administered in the diabetic mice, it led to overexpression of the protein in the pancreatic cells, resulting in increased pancreatic beta cell mass, reduced glucose level and overall reduction in diabetic symptoms. This improved the quality of life and almost doubled the longevity in mice.(15)
This study showed promising results of Follistatin-344 treatment in diabetic patients. Nevertheless, studies in human subjects are still ongoing to determine their safety and efficacy at optimal human dose levels.
Side Effects of the Follistatin-344 Peptide
The clinical safety profile of Follistatin-344 is yet to be established as the studies are still ongoing. However, as with other peptide administrations, some of the common side effects that can be expected with Follistatin-344 use are:
- Redness, inflammation, and numbness at the site of injection (most common)
- Nausea, possible vomiting
While not all drug interactions are known, it has been established that Rapamycin, a common antibiotic medication, causes downregulation of Follistatin and should be avoided when undergoing Follistatin treatment.(16)
Follistatin Market Approval and Availability
Based on 2019 market research,(17) approved Follistatin pharmaceutical formulations were not easily available, though there were chemicals labeled as ‘Follistatin-344’ and ‘Follistatin 315’ available on the (black) market. Out of the 17 tested products, only nine were found to contain Follistatin. The remaining chemicals were found to have growth-promoting peptides (such as MGF and GHRP) present. Interestingly, the nine Follistatin chemicals contained a form of his-tagged Follistatin, which is mainly an isoform found in animals. Therefore, fully understanding the contents is vital before buying any formulation.
Follistatin-344 is a synthetic analogue of the naturally occurring Follistatin human protein. Due to similar structure and properties, this peptide functions via similar mechanisms through the activin binding pathway. Follistatin binds and inhibits the functions of activin and other proteins belonging to the TGF-beta family.
Research so far has shown that Follistatin-344 can be used to treat various types of cancer and reduce the prognosis of diabetes. It is also proven to increase muscle mass, induce muscle growth and cause cell proliferation. Phase I clinical trials in men have also shown the peptide’s ability to induce hair growth and treat male alopecia.
It should be noted that Follistatin-344 is yet to be clinically approved as trials are still ongoing to explore the effects of the peptide in humans and establish its safety and efficacy profile in the therapeutic world.
- 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/
- 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
- skenderian A, Liu N, Deng Q, Huang Y, Shen C, Palmieri K, Crooker R, Lundberg D, Kastrapeli N, Pescatore B, Romashko A, Dumas J, Comeau R, Norton A, Pan J, Rong H, Derakhchan K, Ehmann DE. Myostatin and activin blockade by engineered follistatin results in hypertrophy and improves dystrophic pathology in mdx mouse more than myostatin blockade alone. Skelet Muscle. 2018 Oct 27;8(1):34. https://pubmed.ncbi.nlm.nih.gov/30368252/
- 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/
- Shi L, Resaul J, Owen S, Ye L, Jiang WG. Clinical and Therapeutic Implications of Follistatin in Solid Tumours. Cancer Genomics Proteomics. 2016 11-12;13(6):425-435. https://pubmed.ncbi.nlm.nih.gov/27807065/
- 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/
- 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/
- van der Poel HG, Hanrahan C, Zhong H, Simons JW. Rapamycin induces Smad activity in prostate cancer cell lines. Urol Res. 2003 Feb;30(6):380-6. https://pubmed.ncbi.nlm.nih.gov/12599018/
- Reichel C, Gmeiner G, Thevis M. Detection of black market Follistatin-344. Drug Test Anal. 2019 Nov;11(11-12):1675-1697. doi: 10.1002/dta.2741. Erratum in: Drug Test Anal. 2020 Oct;12(10):1522-1533. PMID: 31758732. https://pubmed.ncbi.nlm.nih.gov/31758732/
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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.