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Biologic Description
Follistatin, a monomeric secretory glycoprotein encoded by the FST gene, is a critical player in various physiological processes. It is ubiquitously expressed across numerous tissues, with prominent expression in the ovary, pituitary, liver, and skeletal muscle.
The structural composition of follistatin is characterized by three follistatin (FS) domains, each encompassing ten cysteine amino acids, and a 63-residue N-terminal segment, which is pivotal for activin binding. The alternative splicing of the FST gene precursor mRNA transcript gives rise to two major isoforms: FS288 and FS315, which are derived from the FS344 and FS317 variants, respectively.
It's role is as a potent inhibitor of the myostatin pathway and other TGF-β superfamily members, particularly activin. Myostatin, a muscle-specific secretory protein, is a critical regulator of muscle growth, exerting a negative impact on muscle mass.
Follistatin inhibits myostatin by obstructing its binding to activin type II receptors. Additionally, follistatin interacts with the activin-inhibin axis in the pituitary, modulating the secretion of follicle-stimulating hormone (FSH). In liver pathology, follistatin influences the development and progression of liver fibrosis by modulating activin A levels and impacting hepatic stellate cells.
The applications of follistatin span various conditions. In muscular dystrophies like BMD and Duchenne muscular dystrophy (DMD), follistatin's ability to augment skeletal muscle mass offers significant therapeutic benefits, as evidenced by improvements in muscle strength and function in gene therapy trials. Its role in muscle growth also positions it as a potential treatment for sarcopenia and muscle-wasting disorders.
Additionally, its interaction with activin A and hepatic stellate cells suggests its utility in treating liver fibrosis, with studies demonstrating reduced fibrosis and hepatocyte apoptosis following follistatin administration. Given its regulatory role in the TGF-β pathway, follistatin may also be explored for diseases where this pathway is implicated, including certain cancers and fibrotic diseases.
Follistatin's role in cancer appears to be linked to its function as an antagonist of members of the transforming growth factor-beta (TGF-β) family, particularly activin and bone morphogenetic proteins (BMPs). This antagonistic action can influence the processes of tumorigenesis, metastasis, and angiogenesis in solid tumors. Follistatin achieves this by modulating the effects of activin and BMPs, leading to alterations in the pathological functions within the tumor microenvironment.
The integration of the optic nerve during embryogenesis is a pivotal determinant of visual acuity in humans. It is understood that the Transforming Growth Factor-beta (TGF-β) pathway is instrumental in the remodeling of the extracellular matrix, which is crucial for the optic nerve fusion. Elevated levels of certain TGF-β superfamily members, notably Bone Morphogenetic Proteins (BMPs), have been implicated in the disruption of optic nerve fusion, potentially leading to congenital blindness. The strategic inhibition of these proteins can negate their suppressive impact, facilitating optic nerve fusion and maintaining the integrity of the optic nerve, thereby significantly diminishing the incidence of blindness associated with developmental anomalies. Ongoing foundational research is exploring the administration of follistatin during pivotal gestational periods to safeguard against optic nerve developmental anomalies, highlighting its potential as a prophylactic agent against congenital blindness.
Investigations into the therapeutic potential of follistatin in trichology have demonstrated promising outcomes. Specifically, follistatin, particularly when employed synergistically with other agents known to stimulate hair growth, has shown a substantial enhancement in hair follicle density and thickness. Clinical trials involving a cohort of 26 participants revealed a 20% augmentation in hair density and an approximate 13% increment in overall hair thickness, with the therapeutic gains persisting for at least one year post-treatment. This was achieved via a single intradermal administration of a complex comprising follistatin and Wnt-signaling pathway modulators. These findings underscore follistatin's therapeutic capacity as a potent adjuvant in hair regeneration protocols, meriting further clinical exploration to fully harness its benefits in alopecia management.
Dosage Guidelines
In a research framework aimed at investigating the therapeutic effects of follistatin on muscle growth and hair density, a dosing regimen has been conceptualized. The regimen involves the administration of follistatin, at varying dosages ranging from a minimum of 100 micrograms (mcg) to a maximum of 300 mcg per day. The method of delivery proposed is a subcutaneous injection, given its efficacy in similar peptide-based therapies.
The treatment cycle is designed to last from one to four weeks, depending on the specific aims of the research and the initial responses observed. Daily administration is suggested to maintain consistent serum levels of follistatin and to maximize the potential for measurable outcomes.
At the conclusion of this period, which may extend from a minimum of 10 days up to a maximum of 30 days, the protocol stipulates a cessation of the treatment for a period of one month. This interval serves as a washout phase, allowing for an assessment of the longevity of follistatin's effects and the reversibility of any changes observed during the treatment window.
100 - 300 mcg
Daily
1-4 Week
Side Effects
Follistatin therapy, an evolving field in medical science, presents a unique set of considerations regarding side effects and safety. As a potent regulator of muscle growth through its antagonism of the myostatin pathway, follistatin's primary application has been in the treatment of muscle dystrophies and other growth-related disorders. However, the broad biological activities of this glycoprotein raise concerns about its potential side effects, which are as diverse as the roles it plays in human physiology.
Musculoskeletal complications are a notable concern, as the promotion of muscle growth by follistatin could inadvertently lead to excessive hypertrophy. Such disproportionate growth may put undue strain on connective tissues, manifesting as joint pain and reduced mobility. There is also the potential impact on the reproductive system, particularly given follistatin's role in modulating FSH levels, which could result in menstrual irregularities or reproductive health issues.
The administration of exogenous follistatin raises the possibility of an immune response, including the production of neutralizing antibodies or hypersensitivity reactions. Moreover, cardiovascular health could be indirectly affected by rapid muscle growth, potentially increasing the workload on the heart and even influencing heart muscle size and function, though such effects are speculative and require further research.
Considering the role of growth factors in renal function, follistatin might also affect the kidneys. This is particularly relevant for individuals with pre-existing renal conditions, where close monitoring would be essential. Furthermore, follistatin's interaction with the TGF-β pathway—a pathway known to be involved in tumorigenesis—suggests a theoretical risk of influencing tumor growth, though this relationship is complex and not yet fully elucidated.
The safety profile of follistatin is also dependent on the dosing regimen. Establishing a safe and effective dose is critical to minimize the risks of both subtherapeutic effects and potential toxicity. Moreover, the long-term safety profile of follistatin remains largely unknown, as chronic side effects may emerge with prolonged use that has not been observed in shorter-term studies.
Special consideration must be given to different patient populations, as children, the elderly, and individuals with specific genetic backgrounds may exhibit distinct responses to follistatin therapy. This necessitates a personalized approach to dosing and vigilant monitoring for adverse effects.
References:
Follistatin-Like Proteins: Structure, Functions and Biomedical Importance
Main forms of cellular signal transmission are known to be autocrine and paracrine signaling. Several cells secrete messengers called autocrine or paracrine agents that can bind the corresponding receptors on the surface of the cells themselves or their microenvironment. Follistatin and follistatin-like proteins can be called one of the most important bifunctional messengers capable of displaying both autocrine and paracrine activity. Whilst they are not as diverse as protein hormones or protein kinases, there are only five types of proteins. However, unlike protein kinases, there are no minor proteins among them; each follistatin-like protein performs an important physiological function. These proteins are involved in a variety of signaling pathways and biological processes, having the ability to bind to receptors such as DIP2A, TLR4, BMP and some others. The activation or experimentally induced knockout of the protein-coding genes often leads to fatal consequences for individual cells and the whole body as follistatin-like proteins indirectly regulate the cell cycle, tissue differentiation, metabolic pathways, and participate in the transmission chains of the pro-inflammatory intracellular signal. Abnormal course of these processes can cause the development of oncology or apoptosis, programmed cell death. There is still no comprehensive understanding of the spectrum of mechanisms of action of follistatin-like proteins, so the systematization and study of their cellular functions and regulation is an important direction of modern molecular and cell biology. Therefore, this review focuses on follistatin-related proteins that affect multiple targets and have direct or indirect effects on cellular signaling pathways, as well as to characterize the directions of their practical application in the field of biomedicine.
Publication Date: April 2021
Follistatin (FS) is a binding protein, abundantly expressed in gonads, pituitary, and other tissues
Follistatin is a monomeric glycoprotein structurally unrelated to inhibin and activin. There are three alternatively spliced products of the single follistatin gene: follistatin 288, follistatin 303, and follistatin 315. Follistatin 288 lacks the carboxyl-terminal acidic region of follistatin 315. Additionally, follistatin-like 3 (follistatin-related protein) is identified, which has a similar structure to follistatin. Follistatin is generally coexpressed with activin and most highly expressed in the ovary and pituitary, but also in a variety of cells and tissues. Follistatin binds activin with high affinity and nullifies its biological actions by preventing its binding and subsequent activation of type I and II activin receptors. This chapter briefly introduces the structure of the follistatin family and its biological functions in relation to the pluripotent effects of activin.
Published: May 2017
Structural Characterization of Follistatin: A Novel Follicle-Stimulating Hormone Release-Inhibiting Polypeptide from the Gonad
Follistatin, a novel, single chain, glycosylated polypeptide bearing no homology with previously characterized inhibins but exhibiting potent and specific pituitary FSH-release inhibition has been structurally characterized by protein microsequencing, cDNA cloning, and DNA sequencing. Two populations of clones differing in their 3′-untranslated sequences were found to encode a 344 amino acid precursor protein and an identical but carboxyl terminal truncated 317 amino acid precursor, respectively. Additionally, one clone, FS18, contained two introns and probably resulted from reverse transcription of heterogeneous nuclear RNA during cDNA library construction. Follistatin is unusually cysteine-rich, containing 36 cysteines in the mature coding sequence of 315 amino acids and an extremely acidic carboxyl terminal region, FS(292-304), comprised of Glu-Asp-Thr-Glu-Glu-Glu-Glu-Glu-Asp-Glu-Asp-Gln-Asp which probably resides outside a tightly crosslinked protein sphere. The heparin-binding ability of follistatin can probably be ascribed to the basic region specified by FS(75-86), Lys-Lys-Cys-Arg-Met-Asn-Lys-Lys-Asn-Lys. Overall, follistatin is organized into three homologous domains, FS(66-135), FS(139-210), and FS(216-287) containing 70, 72, and 72 amino acids, respectively, which show a 52% homology among themselves and a 57% homology with the 56 amino acid human pancreatic secretory trypsin inhibitor protein when aligned for maximum homology.
Published: 1987 Nov
Follistatin Gene Therapy Improves Ambulation in Becker Muscular Dystrophy
Senescent cells accumulate in tissues over time as part of the natural ageing process and the removal of senescent cells has shown promise for alleviating many different age-related diseases in mice. Cancer is an age-associated disease and there are numerous mechanisms driving cellular senescence in cancer that can be detrimental to recovery. Thus, it would be beneficial to develop a senolytic that acts not only on ageing cells but also senescent cancer cells to prevent cancer recurrence or progression.
Authors: Michael A. Valentino, Jieru E. Lin, and Scott A. Waldman
Published: Sept 2015
Follistatin attenuates early liver fibrosis: effects on hepatic stellate cell activation and hepatocyte apoptosis
The positive expression rate of FOXO4 protein in colorectal cancer tissues was 47.50%, which was significantly lower than that in matched noncancerous tissues (91.25%, P<O. 01). Statistical analysis showed that the expression of FOXO4 in colorectal cancer tissues were not obviously correlated with the patients' age, gender , tumor sizes and depth( P >0.05) . however, there were significant differences of FOXO4 expression in tumor differentiation, TNM stage and lymph node metastasis (P<0.05).
Authors: Liu Xiang-qiang, Tang Shan-hong, Zhang Zhi-yong, Jin Hai-feng
Published: 2005 Aug
Clinical and Therapeutic Implications of Follistatin in Solid Tumours
Follistatin (FST), as a single-chain glycosylated protein, has two major isoforms, FST288 and FST315. The FST315 isoform is the predominant form whilst the FST288 variant accounts for less than 5% of the encoded mRNA. FST is differentially expressed in human tissues and aberrant expression has been observed in a variety of solid tumours, including gonadal, gastric and lung cancer, hepatocellular carcinoma, basal cell carcinoma and melanoma. Based on the current evidence, FST is an antagonist of transforming growth factor beta family members, such as activin and bone morphogenetic proteins (BMPs). FST plays a role in tumourigenesis, metastasis and angiogenesis of solid tumours through its interaction with activin and BMPs, thus resulting in pathophysiological function. In terms of diagnosis, prognosis and therapy, FST has shown strong promise. Through a better understanding of its biological functions, potential clinical applications may yet emerge.
Published: 2016 Dec