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8.1.4 Follistatin
Follistatin is an autocrine glycoprotein encoded by the FST gene. Its primary function is binding and bioneutralization of members of the TGF-β superfamily. Follistatin inhibits BMP signaling by binding to BMPs, forming a trimeric complex (Iemura et al., 1998). It binds BMP2, BMP4, and BMP7, with a higher affinity for BMP7. Also, follistatin-like 1 (Fstl1) is a secreted protein of the BMP inhibitor class. It is shown that Fstl1 is a crucial regulator in BMP signaling during mouse development and in mouse lung development (Geng et al., 2011; Sylva et al., 2011). Inoue et al. detected the follistatin mRNA in the callus of repairing bone after fracture thus emphasizing the importance of follistatin in bone system in vivo (Inoue et al., 1994).
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Follistatin
Follistatin is a monomeric glycoprotein produced by the ovary as well as anterior pituitary folliculostellate cells. It is a high affinity activin binding protein therefore its main role in female reproduction is to sequester activin and inhibit FSH secretion.
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Follistatin
It is known that members of the TGF-β superfamily can influence regulation of overall energy homeostasis by inflecting brown adipocyte characteristics. When inactivating TGF-β/Smad3/myostatin signaling, it has been shown in mice that browning of white adipocytes is promoted [45]. Pervin et al. created in vivo and in vitro models that showed when targeting TGF-β/myostatin signaling, the functions of BAT is enhanced and other factors like energy balance and reducing insulin resistance were also affected in a positive manner. The soluble glycoprotein Follistatin is a member of the TGF-β super family and has been shown to bind and antagonize the actions of myostatin during BAT differentiation and regulation of cellular metabolism. Follistatin is released by the liver and follistatin levels are increased during exercise [46]. More precisely, after 3 hour of bicycle exercise, plasma follistatin increased 3 hour into recovery with a peak of sevenfold. It was further shown in humans, that the liver secretes follistatin at rest and during exercise, and the glucagon-to-insulin ratio is a key determinant of circulating follistatin levels [47] Exercise leads to hepatic release of follistatin and a subsequent increase in plasma-follistatin levels in humans. Follistatin has the potential to induce browning, but evidence for its effect on human adipocytes are lacking.
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1.1.5 Follistatin
Follistatin (FST) was first identified in the 1980s as a secreted glycoprotein that is found in most tissues throughout the body. FST acts as a multi-faceted hepatokine that is involved in reproduction [181], muscle growth [182], cancer development [183], and metabolism [184]. FST acts as an inhibitor of members of the TGF-β superfamily, including myostatin and activins [185,186], and can function as a promoter of skeletal muscle growth [187]. Most of FST's effects on reproductive health and cancer development are related to its interactions with activins and follicle-stimulating hormone, while its effects on muscle growth result from interactions with myostatin [186]. FST is secreted by a broad range of cell types, and plasma levels are thought to result from paracrine/autocrine signaling spillover [188]. However, recent work indicated that the liver is a key contributor to circulating levels of FST in humans [188–190]. Patients with type 2 diabetes have slightly elevated levels of circulating FST and plasma levels associated with glycemic parameters in these patients [188,191,192] (Table 1). Similarly, serum levels of FST are also significantly increased in individuals with NAFLD [193]. FST is present in three main isoforms, FST288, FST303, and FST315, with FST315 being the predominant isoform found in the circulation [185,194,195]. Although the physiological role of circulating FST is not fully understood, it is thought that FST is acutely regulated by the glucagon-to-insulin ratio [190]. Under conditions of prolonged fasting or increased energy demands (such as exercise), FST is significantly upregulated in response to increased and decreased amounts of glucagon and insulin, respectively [190]. Unlike other “energy deprivation” hepatokines that function to improve the metabolic profile, the function of physiological increases in FST during energy deprivation is not yet fully understood. Overexpression of FST in mice resulted in insulin resistance in WAT, increased hepatic glucose production, and impaired whole-body glucose tolerance, consistent with higher expression in patients with type 2 diabetes [77,196]. Furthermore, knockdown of FST in mice improved insulin sensitivity [29,196].
Although increased chronic levels of FST may be metabolically detrimental, acute expression of FST during exercise appears to be beneficial as it results in FFA and glucose uptake in skeletal muscle. FST has also been shown to promote brown adipocyte differentiation in mice [197]. A recent study demonstrated that mice overexpressing FST have increased expression of thermogenic markers, including UCP1, in WAT and BAT [198]. FST functions to increase the phosphorylation of MAPK/ERK1/2 proteins in WAT and increase the expression of Myf5 protein in BAT, which increases UCP1 expression in both tissues [198]. While there is a potential therapeutic role for acute FST treatment, more research is needed to determine the acute and chronic effects of FST in metabolic dysfunction.
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Chapter
Target Cells/Tissues and Functions
Follistatin 288 is associated with proteoglycan on the cell surface because of its high affinity for heparan sulfate, and antagonizes the effects of activins by blocking the binding of activin to their receptors. Complexes of follistatin and activins associated with proteoglycan are then endocytosed and degraded by lysosomal enzymes. Follistatin 315 with low affinity for heparan sulfate is the predominant form in the human circulation but its exact role is unclear. Follistatin-like 3 that lacks heparan sulfate binding sites is considered to circulate but its exact function is unclear. Follistatin can neutralize the responses induced by exogenous or endogenous activins in various cells and tissues (Table 33C.1 [7–18]; also see Table 33B.2 in subchapter 33B). In addition, follistatin binds to several members of the transforming growth factor (TGF) β family and blocks the interaction of these cytokines with their cognate receptors.
Table 33C.1. Effects of Follistatin on Activin Effects in Various Cells or Tissues
Cells or Tissues Species Responses Induced by Activin Follistatin Effects, (Solely Induced) Ref gonadotroph rat ↑FSH production neutralizing the activin effect (↓basal FSH production) [7] granulosa cell rat ↑FSH-induced progesterone production neutralizing the activin effect [8] rat ↑inhibin production neutralizing the activin effect [8] rat ↑FSH/LH receptor expression neutralizing the activin effect [8] luteinized human ↓basal progesterone production neutralizing the activin effect [9] oocyte zebrafish ↑germinal vesicle breakdown (GVBD) neutralizing the activin effect [10] rat ↑GVBD neutralizing the activin effect (↓GVBD) [11] embryo frog ↑mesoderm induction neutralizing activin effect [12] cattle ↑early embryonic development neutralizing activin effect (↓early embryo development) [13] gonocyte rat ↑proliferation neutralizing the activin effect [14] adenocortex cell cattle ↓ACTH-induced cortisol and androgen production partially neutralizing the activin effect [15] bone marrow mouse ↑colony formation of erythroid progenitor cell neutralizing the activin effect (↓colony formation) [16] pancreatic cell rat ↑glucose stimulated insulin release from β cells neutralizing the activin effect [17] hepatocyte rat ↑apoptosis neutralizing the activin effect [18]
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III.A Inhibition of Signaling at the Cell Surface
Activin signaling can be blocked at the receptor level by two types of molecules, follistatins and inhibins. Follistatins are binding proteins of activins that neutralize activin actions in many biological systems by controlling the accessibility of activins to their receptors. There are two major forms of follistatins, FS-288 and FS-315, generated from alternative splicing of the same gene. Each β-subunit can bind to one follistatin and therefore, the activin–follistatin complex consists of one activin molecule and two follistatin molecules. The affinity of follistatin binding to activins is similar to that between activins and their receptors. Follistatins neutralize activin bioactivity by inhibiting the binding of activins to their type II receptors. In addition, FS-288 inhibits activin action by increasing the endocytotic degradation of activin through the association with cell surface heparan sulfate.
Inhibins are structurally related to activins by sharing the same β-subunit. It is well documented that inhibins block many actions of activins and function as activin antagonists. Several studies have shown that inhibins can bind to ActR-IIA and, therefore, antagonize activin actions. The binding affinity of inhibins to ActR-IIA is 10-fold lower than that between activins and ActR-IIA; however, it has been recently shown that betaglycan, a proposed TGF-β type III receptor, can bind to inhibins with high affinity and that the binding of inhibins to betaglycan results in an increased affinity of inhibin binding to ActR-IIA. It was therefore suggested that inhibins bind to betaglycan and ActR-IIA and block activin signaling by competing with activins for their type II receptors.
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Tissue Distribution of mRNA
The follistatin gene is expressed in most tissues where activin mRNAs are detected: hypothalamus, pituitary, ovary, testis, liver, bone marrow, embryo, uterus, placenta, skin, blood vessel. The follistatin like-3 gene is expressed in the ovary, testis, adrenal gland and heart.
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Abstract
Introduction and aim
Myostatin and follistatin are the main hormones for regulating muscle mass, and previous research suggests they are modulated by resistance training. We therefore performed a systematic review and meta-analysis to investigate the impact of resistance training on circulating myostatin and follistatin in adults.
Methods
A search was conducted in PubMed and Web of science from inception until October 2022 to identify original studies investigating the effects of resistance training compared with controls that did not exercise. Standardized mean differences and 95% confidence intervals (CIs) were calculated using random effects models.
Results
A total 26 randomized studies, including 36 interventions, and involving 768 participants (aged ∼18 – 82 years), were included in the meta-analysis. Resistance training effectively decreased myostatin [-1.31 (95% CI −1.74 – −0.88, p = 0.001, 26 studies] and increased follistatin [2.04 (95% CI: 1.51 – 2.52), p = 0.001, 14 studies]. Subgroup analyses revealed a significant decrease in myostatin and increase in follistatin regardless of age.
Conclusion
Resistance training in adults is effective for reducing myostatin and increasing follistatin which may contribute to the beneficial effects of resistance training on muscle mass and metabolic outcomes.
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IV.E Follistatin-Binding Proteins
Prior to any signaling event, activins can be bound to binding proteins such as follistatins (FSs). In many tissues, the interplay between activins and FSs provides a potent mechanism to regulate the access of the ligands to their receptors. Follistatins are encoded from a single gene located on chromosome 5q11.2 and alternative splicing of the mRNA generates different molecular weight isoforms. The FS proteins include an “FS domain” of 10-cysteine structures and an extracellular calcium-binding domain that makes them structurally homologous with epidermal growth factor (EGF), a group of enzyme inhibitors of the Kazal family, and other proteins such as SPARC, agrin, testican, and follistatin-related protein (FSRP). The function of the FS domains is not known but binding to activins differentiates follistatins from other members.
The biological activity of FS is mediated via its high-affinity binding to activins. The binding is nearly irreversible and prevents ligand access to receptors on the cell surface, making FS binding a critical regulator of activin bioactivity in cells in which FS is expressed. FS also contains a heparin-binding domain that permits high-affinity association with cell surface heparin-sulfated proteoglycans (HSPGs). When activins are bound to FS–HSPG complexes at the cell surface or in the extracellular matrix, access to the receptors is restricted and hence the paracrine actions of locally or systemically derived ligands are inhibited. As well as activins, FS binds and neutralizes the mesoderm-inducing actions of other members of the TGF-β superfamily, such as BMP-2, -4, and -7, although the affinity of FS for the BMPs is significantly lower than that for the activins.
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8 Surrogates for gene replacement using a muscle building strategy
Blocking the myostatin pathway shows dramatic muscle building properties that are highly conserved across species, including mice, sheep, cattle, canines, and humans [24,25,34,39]. Myostatin is a member of the transforming growth factor (TGF)-β superfamily and numerous studies have demonstrated that it is a negative regulator of skeletal muscle growth. An antibody to myostatin (MYO-29) was not beneficial to patients in a clinical trial [42]. Follistatin is a powerful inhibitor of myostatin plus having the advantage of controlling muscle mass through pathways independent of the myostatin signaling cascade [21]. In studies of the myostatin knockout mice crossed to mice carrying a follistatin transgene there was a quadrupling of muscle mass compared with the doubling of muscle mass that is observed from lack of myostatin alone.
In preparation for taking this to clinical trial, we identified an alternatively spliced isoform of follistatin (FS344) that can be packaged in AAV1. Upon intramuscular injection, FS344 undergoes post-translational modification and generates a stable, FS315 isoform with minimal toxicity. In normal C57Bl/6 mice and in the mdx mouse, intramuscular injections of AAV1 carrying the FS344 gene increased muscle mass (histological measure) and quantitative strength, as assessed by hind- and forelimb grip and measures of force generation and protection against eccentric contractions [12]. The benefits persist for more than two years, and in older mice not treated until 210 days of age, muscle strength increased for 60 days post gene delivery and persisted long-term, throughout the 560 days of evaluation. Study of the muscle and multiple organs from these mice revealed no significant abnormalities. In addition, we have tested the safety and efficacy of AAV1.CMV.FS344 in non-human primates showing no organ system toxicity for as long as 15 months and an ability to increase quadriceps muscle size and strength following direct muscle injection [19]. This occurred without adverse effects. Necropsies showed no abnormalities in heart, lungs, liver, kidneys, or gonads. We also monitored clinical chemistries and hormone levels related to gonadal function including follicle stimulating hormone, luteinizing hormone, testosterone, and estradiol. No abnormalities were encountered.
We have now taken this to clinical trial in two patient groups who could specifically benefit by increasing size and strength of the quadriceps muscle similar to our proof of principle studies in mdx mice and cynomolgus macaques (http://clinicaltrials.gov/). In Becker muscular dystrophy and in sporadic inclusion body myositis the quadriceps muscle is targeted by the disease process leading to frequent falls and ultimately loss of ambulation. The gene delivery protocol approved by the FDA calls for injection of 12 sites in the quadriceps muscle divided evenly between rectus femoris, vastus medialis, and vastus lateralis. Vector administration includes a low dose cohort receiving intramuscular injections on one side only (2 × 1011 vg/kg); intermediate dosing (6 × 1011 vg divided between extremities) and high level dosing (1.2 × 1012 vg/kg divided between extremities). Three patients in the low dose cohort have been injected at the time of this writing. No adverse effects have been encountered. Muscle biopsies will be done at 6 months in all patients to delineate fiber size. MRI of the quadriceps muscle will also be used to assess muscle volume. Additional testing includes the 6 min walk test, climbing 4 standard steps, timed to get up from a chair, and strength of knee extensors using quantitative myometry.
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