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Follistatin

Follistatin is a molecule that suppresses three protein messengers in the body, one of which is Myostatin; by inhibiting Myostatin's inhibition of protein synthesis, follistatin may increase muscle mass. It may get affected by exercise and diet, but is understudied.

Our evidence-based analysis on follistatin features 34 unique references to scientific papers.

Research analysis led by Kamal Patel .
Reviewed by
Examine.com Team
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Summary of Follistatin

Primary Information, Benefits, Effects, and Important Facts

Follistatin is a negative regulatory protein. It works to regulate the body by suppressing the actions of other proteins and hormones.

When overexpressed, it can cause excessive suppression of these proteins. One of these proteins, Myostatin, is itself a negative regulatory of muscle protein synthesis. Thus, increases in follistatin expression indirectly promote muscle protein synthesis by eliminating a 'lock' on protein synthesis.

Follistatin overexposure (typically though injections) mimics myostatin deficiency, which is colloquially known as 'double muscling' and is the cause of hypermuscularity seen in Belgian Blue Cattle.

Follistatin also has interactions with reproductive health, and may have far-reaching effects due to its suppression of proteins that are not myostatin; namely Activins.

Research Breakdown on Follistatin

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Follistatin is a glycosylated protein found in plasma that was named due to its ability to suppress Follicle-Stimulating Hormone (FSH).[1] It is a member of the Transforming Growth Factor Beta (TGF-b) superfamily of proteins.

Follistatin seems to be able to bind to and inactivate proteins through preventing said proteins from acting on their receptors. This is seen with:

Myostatin is the prototypical negative muscle mass regulator[6], GDF11 is unlikely to regulate muscle mass as it is more involved with skeleton and kidney regulation[7] and activins regulate muscle mass in addition to a pleiotropic effect on many other organs such as brain and ovaries.[8][9] An increase in follistatin levels may cause a decrease in the activity of the above proteins.

Although involved with reproduction, plasma follistatin levels do not seem to vary during different phases of menstruation nor does it seem to vary throughout reproductive age.[10][11]

Follistatin gene expression appears to be reduced during menopause, and is elevated with Hormone-Replacement Therapy.[12]

Follistatin seems to be highly concentrated in seminal fluid[13] and its concentration is independent of fertility state.[14]

Follistatin manipulations have been looked at indirectly through its ability to block Myostatin signalling.[3] Myostatin is a negative regulator (suppressor) of muscle protein synthesis, and thus inhibiting the negative regulation allows for muscle protein synthesis to accelerate.[15][16][17] Administration of a drug that works vicariously through follistatin has been shown in mice to enhance muscle growth long-term.[18]

Follistatin works via suppressing Myostatin, but also seems to suppress activin. Even in myostatin deficient mice, follistatin overexpression can further increase protein synthesis (suggesting suppression of other negative regulatory factors).[17] The end result is more satellite cell recruitment.[6]

Follistatin increases seen during exercise seem to originate from the liver, and are independent of related exericse-induced factors IL-6 and adrenaline.[19]

Mouse models with Follistatin-derived peptides (to create selectivity for Myostatin over other activins) tends to result in increased muscle mass and less fat mass with smaller adipocytes.[20][21][22] Myostatin deficiency, either by follistatin intervention or genetic knockout, results in an inability to store excessive fat.[23][24]

Genetic manipulations into myostatin (used as a model for lack of myostatin activity on its receptors) seems to result in muscle growth across species. The above mouse models, cattle,[25][26], dog[27], sheep[28], and a genetic abnormality case study in a human.[29] Using follistatin gene transplantation, a 20% reduction of myostatin's effects is able to confer significant muscle growth in primates.[30]

Follistatin mRNA increases after eccentric exercise in menopausal women by 2.1-fold, and 5.8-fold with Hormone Replacement therapy.[12] 

When mRNA is measured 24 hours after the eccentric exercise, it is not significantly different from baseline values.[31]

In healthy males, 3 hours of cardiovascular exercise at 50% VO2 max or 2 hours of intermittent eccentric activity (weightlifting) was able to increase follistatin 7-fold relative to fasting. However, this increase was noted 5-6 hours after the start of exercise, and not during.[19] It seems that the follistatin is created in the liver and not muscles; this was supported by a mouse model showing a 21.5-fold increase in liver mRNA of follistatin.[19]

In muscle tissue, follistatin seems to be created in response to necrosis (damage)[32] from either exercise or chemical agents.

One study in healthy males found that, upon waking, follistatin was increase 154% above baseline (approximately 3000pg/mL relative to 1000pg/mL) for as long as subjects fasted.[33]

A single time injection, combined with the growth factors VEGF and KGF, shows promise in hair regrowth without repeated administrations needed.[34]

References

  1. ^ Phillips DJ, de Kretser DM. Follistatin: a multifunctional regulatory protein. Front Neuroendocrinol. (1998)
  2. ^ Amthor H, et al. Follistatin complexes Myostatin and antagonises Myostatin-mediated inhibition of myogenesis. Dev Biol. (2004)
  3. ^ a b Zhu X, et al. Myostatin signaling through Smad2, Smad3 and Smad4 is regulated by the inhibitory Smad7 by a negative feedback mechanism. Cytokine. (2004)
  4. ^ Gamer LW, et al. Gdf11 is a negative regulator of chondrogenesis and myogenesis in the developing chick limb. Dev Biol. (2001)
  5. ^ Tsuchida K. Activins, myostatin and related TGF-beta family members as novel therapeutic targets for endocrine, metabolic and immune disorders. Curr Drug Targets Immune Endocr Metabol Disord. (2004)
  6. ^ a b Follistatin induces muscle hypertrophy through satellite cell proliferation and inhibition of both myostatin and activin.
  7. ^ McPherron AC, Huynh TV, Lee SJ. Redundancy of myostatin and growth/differentiation factor 11 function. BMC Dev Biol. (2009)
  8. ^ Intraovarian Activins Are Required for Female Fertility.
  9. ^ Molecular heterogeneity of follistatin, an activin-binding protein. Higher affinity of the carboxyl-terminal truncated forms for heparan sulfate proteoglycans on the ovarian granulosa cell.
  10. ^ Khoury RH, et al. Serum follistatin levels in women: evidence against an endocrine function of ovarian follistatin. J Clin Endocrinol Metab. (1995)
  11. ^ Hurwitz JM, Santoro N. Inhibins, activins, and follistatin in the aging female and male. Semin Reprod Med. (2004)
  12. ^ a b Influence of hormone replacement therapy on eccentric exercise induced myogenic gene expression in postmenopausal women.
  13. ^ Anderson RA, et al. Follistatin and activin A production by the male reproductive tract. Hum Reprod. (1998)
  14. ^ Muttukrishna S, et al. Serum activin A and follistatin in disorders of spermatogenesis in men. Eur J Endocrinol. (2001)
  15. ^ Lee SJ. Regulation of muscle mass by myostatin. Annu Rev Cell Dev Biol. (2004)
  16. ^ Regulation of myostatin activity and muscle growth.
  17. ^ a b Lee SJ. Quadrupling muscle mass in mice by targeting TGF-beta signaling pathways. PLoS One. (2007)
  18. ^ Long-term enhancement of skeletal muscle mass and strength by single gene administration of myostatin inhibitors.
  19. ^ a b c Hansen J, et al. Exercise induces a marked increase in plasma follistatin: evidence that follistatin is a contraction-induced hepatokine. Endocrinology. (2011)
  20. ^ Lee SJ, McPherron AC. Regulation of myostatin activity and muscle growth. Proc Natl Acad Sci U S A. (2001)
  21. ^ Nakatani M, et al. Transgenic expression of a myostatin inhibitor derived from follistatin increases skeletal muscle mass and ameliorates dystrophic pathology in mdx mice. FASEB J. (2008)
  22. ^ Nakatani M, et al. Follistatin-derived peptide expression in muscle decreases adipose tissue mass and prevents hepatic steatosis. Am J Physiol Endocrinol Metab. (2011)
  23. ^ McPherron AC, Lee SJ. Suppression of body fat accumulation in myostatin-deficient mice. J Clin Invest. (2002)
  24. ^ Hamrick MW, et al. Resistance to body fat gain in 'double-muscled' mice fed a high-fat diet. Int J Obes (Lond). (2006)
  25. ^ Grobet L, et al. A deletion in the bovine myostatin gene causes the double-muscled phenotype in cattle. Nat Genet. (1997)
  26. ^ Grobet L, et al. Molecular definition of an allelic series of mutations disrupting the myostatin function and causing double-muscling in cattle. Mamm Genome. (1998)
  27. ^ Mosher DS, et al. A mutation in the myostatin gene increases muscle mass and enhances racing performance in heterozygote dogs. PLoS Genet. (2007)
  28. ^ Clop A, et al. A mutation creating a potential illegitimate microRNA target site in the myostatin gene affects muscularity in sheep. Nat Genet. (2006)
  29. ^ Schuelke M, et al. Myostatin mutation associated with gross muscle hypertrophy in a child. N Engl J Med. (2004)
  30. ^ Follistatin Gene Delivery Enhances Muscle Growth and Strength in Nonhuman Primates.
  31. ^ Jensky NE, et al. The influence of eccentric exercise on mRNA expression of skeletal muscle regulators. Eur J Appl Physiol. (2007)
  32. ^ Hiroki E, et al. A comparative study of myostatin, follistatin and decorin expression in muscle of different origin. Anat Sci Int. (2011)
  33. ^ Vamvini MT, et al. Energy deprivation alters in a leptin- and cortisol-independent manner circulating levels of activin A and follistatin but not myostatin in healthy males. J Clin Endocrinol Metab. (2011)
  34. ^ Zimber MP, et al. 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)