Follistatin-344 Peptide Useful for Muscle Growth and Lean Muscle Mass, Helps Induce Hair Growth, Combat Insulin Deficiency, Other Potential Benefits
Follistatin is a naturally occurring glycoprotein that is present in almost all tissues in the body. This is an autocrine chemical (1), meaning the cell, through a form of cell signal, produces a chemical messenger which binds to the autocrine receptors of the same cell, resulting in modifications to the cell.
Follistatin is naturally available in two isoforms, namely, FST 317 and FST 344, each composed of 317 and 344 amino acids. These two isoforms are produced due to an alternative splicing process of the mRNA (2).
At the time of initial discovery and isolation, Follistatin was believed to primarily inhibit the secretion of gonadal hormone follicle-stimulating hormone (FSH). However, over the time with 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 (1).
While the peptide is naturally formed in the body, a synthetic version of the full size endogenous human protein is also available to combat any Follistatin deficiencies pertaining to increased age or other bodily defects.
Introduction to Follistatin-344 Peptide
Follistatin-344 is a synthetic version of the endogenous Follistatin-344 human protein isoform.
Although the number of amino acids differ in the Follistatin isoforms, at its core, the human protein is composed of 63 amino acid residues along with three domains, namely FSD1, FSD2 and FSD3. The same applies to the synthetic peptide (3).
Follistatin was first discovered in 1987, upon isolation from the bovine and porcine follicular fluid (3), where the primary function of the protein was believed to be solely limited to the inhibition of follicle stimulating hormone (1).
Later, upon further research, it was established that the peptide has the ability to bind and neutralize activin and myostatin, and this binding is almost irreversible due to its steady dissociation rate(1).
Role of the Peptide
Follistatin-344 is mainly able to exert its effect due to its ability to bind with activin(4).
Follistatin has a collaborative role in the reproductive functioning along with other chemicals such as activin and inhibins. Activin is mainly released by the ovarian follicle 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 is not entirely understood, it has been established that Follistatin is locally produced in the pituitary gland and gonads, testes and ovaries. Furthermore, Follistatin is widely 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 Peptide
The various benefits of Follistatin-344 include:
- Improved muscle growth
- Enhanced cell proliferation
- Increased lean muscle mass
- Possess liver protection abilities
- Ability to induce hair growth
- Capability 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 that hinder the muscle cell differentiation and growth. Myostatin protein belongs to the transforming growth factor-beta (TGF-beta) protein which is known to be inhibited by Follistatin.
During the 1997 study (5), it was noted that mice, when treated with Follistatin, had reduced levels of myostatin, which helped improve skeletal muscle mass with each mice weighing 2 to 3 times more than usual. This led the scientists to believe that Follistatin could potentially be useful in treating disorders such as muscle dystrophy, which is characterized by poor muscle growth and development.
In another study (6), Follistatin was induced in mice via nanoparticle mediated 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 treatment mice, administered with this mRNA containing nanoparticles, 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 treatment mice was 10% more than the normal control mice.
Role in Improving Muscular Dystrophy
In this study (7), a mouse model with induced Duchenne muscular dystrophy (also called mdx model) was treated with synthetic Follistatin 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 levels of muscle markers for inflammation and fibrosis. There was obvious, increased improvement in the muscle dystrophy pathway, which showed positive, therapeutic signs of the peptide.
Thus, Follistatin has proven to have benefits in improving muscle mass and development in various animal models which can potentially be useful in human disease management as well.
Role in Cancer Treatment
It was noted, through the reverse transcription polymerase chain reaction study (RT-PCR), that the levels of Follistatin fluctuated in the patients with breast cancer. While most of the patients had lower levels of Follistatin, a handful of patients had higher levels. Patients with high levels had fast growing, but less invasive, tumor cells (8).
A study (9) was conducted where the available gene expression data of the mouse model suffering from breast cancer was examined. It was noticed in most cases Follistatin was under-expressed in carcinogenic breast cells which led to an increased spread of cancer cells which is mainly caused by activin proteins. As Follistatin is known to bind with activin and cause inhibition in its activity, it was found that if Follistatin is restored in these mice, it would prevent the prognosis of activin induced metastasis and thereby help combat the disease by improving the overall survival.
Research(10) has shown that BMP, bone morphogenic protein, is a one of the causative factors in the transition of normal esophageal tissue to cancerous tissues. Treatment with Follistatin helps counteract the acid reflux, which thereby prevents the over activation of BMP and development of esophageal cancer.
Because of its antagonistic function on the TGF-beta proteins, such as activin and BMPs, Follistatin is believed to play a significant role in tumorigenesis, angiogenesis, and metastasis of the cancerous tumors and thereby plays role a cancer diagnosis and therapy(11). While more research is yet to be conducted to fully explore its clinical applications, Follistatin shows a promising potential to be used in cancer treatment.
Role in Cell Proliferation
Research (12) has shown an odd contrast in the working of Follistatin where it inhibits metastasis but promotes cell proliferation. This is probably why the peptide is associated with an increased tumor growth (tumorigenesis) but also linked with a reduced invasion and spread of tumors (metastasis).
Study has shown that hepatocytes (i.e., liver cells) in particular need Follistatin in order to proliferate. When studied in experimental rats, it was seen that inactivation of activin by Follistatin is a precondition for cell proliferation to occur. It is believed that there may be some energy exchange between the cells where the energy used for cell migration is shut off in order to switch with cellular growth and proliferation.
Role in Liver Protection
This 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 two groups, one that was treated with Follistatin and other with control, for four weeks. After these 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 plays a significant role in preventing liver fibrosis and thereby protecting the organ from failure.
Role in Improved Hair Growth
Research has shown that Follistatin and wound healing factors stimulate the inter-follicular stem cells which leads to increased hair growth. A study(14) was conducted where the effects of this synthetic protein formulation, termed as Hair Stimulating Complex (HSC), was studied in subjects with male pattern baldness.
There were 26 candidates who were treated with HSC injections via intradermal route for 52 weeks. All 26 candidates showed well 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 potentially combating baldness and alopecia by inducing improved hair growth mechanisms in males.
Role in Diabetes Management
Diabetes is one of the most common ailments being suffered worldwide, leading to chronic complications and sometimes even death. While it is known to be mainly caused by insulin resistance and insufficiency, there are very few medications available that preserve the pancreatic beta cells functions while overcoming this insulin insufficiency.
Research (15) has shown that when Follistatin was administered in the diabetic mice, it led to the overexpression of the protein in the pancreatic cells which thereby resulted 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.
This study showed promising results of Follistatin treatment in diabetic patients. Nevertheless, studies in human subjects are still ongoing to determine its safety and efficacy at optimal human dose levels.
Side Effects of Follistatin-344 Peptide
The clinical safety profile of Follistatin-344 is yet to be established as the clinical studies are still ongoing and the data are not fully available yet. Hence, little is known about side effects so far.
However, as with other peptide administrations, some of the common side effects that can be expected with Follistatin-344 usage are:
- Redness, inflammation, and numbness at the site of injection (most common)
- Inflammation / swelling
- Nausea, possibly vomiting
While not all drug interactions are known, it has been established that Rapamycin, a common antibiotic medication, causes down regulation of Follistatin (16) and hence should be avoided when undergoing Follistatin treatment.
Market Approval and Availability
Based on 2019 market research (17), it was seen that while approved Follistatin pharmaceutical formulations were not easily available, there were some chemicals labelled as ‘Follistatin-344’ and ‘Follistatin 315’ available in the (black) market.
Of the 17 tested products, only 9 were found to actually 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. Hence, it is vital to fully understand the contents prior to purchasing any formulation.
Follistatin-344 is a synthetic analogue of the naturally occurring Follistatin human protein. Owing to similar structure and properties, they function via a similar mechanism through activin binding pathway. Follistatin is known to bind and inhibit 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 also has proven ability to increase muscle mass, impel muscle growth and cause cell proliferation. Phase I clinical trial in men has also shown its ability to induce hair growth and treat male alopecia.
It should be noted that Follistatin-344 is yet to be clinically approved as clinical trials are still ongoing to fully explore the effects of the peptide in humans and establish its safety and efficacy profile in the therapeutic world.
1. Hiroyuki Kaneko, Handbook of Hormones, 2016. https://www.sciencedirect.com/topics/neuroscience/follistatin
2. FST follistatin [Homo sapiens (human)]. https://www.ncbi.nlm.nih.gov/gene?Db=gene&Cmd=DetailsSearch&Term=10468
3. 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/
4. 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/
5. 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/
6. 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
7. Iskenderian 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/
8. 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/
9. 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/
10. 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/
11. 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/
12. 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/
13. 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/
14. 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/
15. 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/
16. 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/
17. 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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