Search

The activins–follistatins–inhibins (AFI) hormonal system affects bone metabolism. Treatments that alter bone metabolism may also alter the AFI molecules. In this non-randomized, open-label, head-to-head comparative study, circulating levels of the AFI system were evaluated in postmenopausal women with osteoporosis treated for 12 mo with either teriparatide (n = 23) or denosumab (n = 22). Τeriparatide treatment increased activin B (P=.01) and activin AB (P=.004) and the ratios activin A/follistatin (P=.006), activin B/follistatin (P=.007), activin AB/follistatin (P<.001), and activin AB/ follistatin-like 3 (FSTL3) (P=.034). The significant P for trend in group × time interactions of activins B and AB and of the ratio activin AB/FSTL3 remained robust after adjustment for BMI and LS BMD but it was lost for activin B after adjustment for previous antiresorptive treatment. The effect of teriparatide on BMD was attenuated when it was adjusted for baseline activins levels or their 12-mo changes. No changes were observed after denosumab treatment. In conclusion, activins B and AB, as well as the ratios of all activins to follistatin and of activin AB to FSTL3 increased with teriparatide treatment, possibly in a compensatory manner. Future studies are needed to study the potentially important role activins may play in bone biology and any associations with the effect of teriparatide on BMD. Clinical Trials identifier: NCT04206618. ClinicalTrials.gov  https://clinicaltrials.gov/search?term=NCT04206618. Lay Summary: Bone and the muscle comprise 2 tissues that are considered to interact with each other, not only through mechanical but also through endocrine signals. Several components of the activins–follistatins–inhibins (AFI) hormonal system have been shown to be secreted by the muscle and affect the bone possibly contributing to this interplay. We have previously investigated the levels of the AFI molecules in case–control studies and reported differences between osteoporotic vs osteopenic vs postmenopausal and premenopausal women with normal BMD. In this 12-mo, non-randomized, open-labeled, head-to-head comparative study, we prospectively compared the effect of antiosteoporotic agents with opposite effect on bone metabolism, that is, teriparatide vs denosumab, on the circulating concentrations of all known molecules of the AFI system in postmenopausal women with osteoporosis. We observed increases of activins after teriparatide treatment, but no effect after denosumab treatment on any of the AFI molecules studied. Since activins are mainly acting in an autocrine way and since activin B and AB have not been extensively studied, further studies in the basic research, preclinical, and clinical research fields are required to expand these observations and fully elucidate physiology and any therapeutic potential. [ABSTRACT FROM AUTHOR]

Background & Objective: Activin A, a protein in the TGF-ß superfamily, plays a crucial role in reproductive regulation by regulating FSH secretion and activating intracellular signaling pathways. Follistatin regulates FSH secretion, affecting follicle genesis and ovulation, playing a crucial role in reproductive processes, especially in ectopic pregnancy and missed abortions. Missed abortions are often caused by genetic factors like chromosomal abnormalities and maternal hormonal imbalances. Evaluated the blood levels of follistatin and activin A in women diagnosed with ectopic pregnancy and missed miscarriage. Research into how follistatin and activin A regulate physiological processes. Materials & Methods: The study included 120 women between the ages of 18 and 45 years, divided into three groups: normal pregnancies (60 women), ectopic pregnancy (30 women), and missed miscarriage (30 women), the gynecology clinic of Baghdad Teaching Hospital for the period from Sept 2023 to Jan 2024. Results: Activin A and follistatin significantly higher in women with ectopic pregnancy and missed abortions than in the control groups. In addition, compared to patients in the missed abortion group, the ectopic group's incidence was significantly lower. Conclusion: Serum Activin A and Follistatin levels can be used as indicators of ectopic pregnancy and missed abortion. Serum FST level at cut-off (>5.24) can be used as a novel biomarker of women with missed abortions. Activin A is involved in the regulation of ovarian follicle development and corpus luteum function in females. [ABSTRACT FROM AUTHOR]

BACKGROUND: Based on studies from animal models, growth differentiation factor-11 (GDF-11) may have rejuvenating effects in humans. GDF-11 has high sequence homology with GDF-8 (also known as myostatin); follistatin and follistatin-like protein-3 (FSTL-3) are inhibitory proteins of both GDF-8 and GDF-11. METHODS: Using highly specific liquid chromatography with tandem mass spectrometry assays for GDF-11 and GDF-8 and immunoassays for follistatin and FSTL-3, we quantified the association of these factors with muscle size, strength, and physical performance in 2 prospective cohort studies of community-dwelling older adults (Health, Aging, and Body Composition study [Health ABC] and Cardiovascular Health Study [CHS]). RESULTS: GDF-8 levels were positively associated with thigh muscle cross-sectional area and density in Health ABC (data not available in CHS). GDF-8 levels were positively associated with lean mass (a surrogate of muscle mass) in Health ABC but not CHS, and grip strength in CHS but not Health ABC. FSTL-3 (and perhaps follistatin) was negatively associated with lean mass and had variable associations with other variables. In contrast, GDF-11 was not significantly associated with strength or performance. CONCLUSIONS: GDF-8 and its binding proteins, follistatin and FSTL-3, may constitute a counterregulatory system (chalones) to restrain age-related loss of muscle mass and strength.

BACKGROUND: Studies using heterochronic parabiosis discovered that circulating factors mediate brain aging in animal models. METHODS: We assessed growth differentiation factors (GDF)-11 and GDF-8 using mass spectrometry and inhibitors follistatin and follistatin-like protein-3 (FSTL-3) with ELISA in the Cardiovascular Health Study (CHS; N = 1 506) and the Health, Aging and Body Composition (Health ABC) Study (N = 1 237). CLL-11 and beta-2 microglobulin (β2M) were measured with ELISA in a subset of 400 individuals in Health ABC. Associations were assessed with cognitive function, brain magnetic resonance imaging (MRI) findings (CHS only), and incident dementia using correlations, linear regression, and Cox proportional hazards models. RESULTS: In CHS, levels of GDF-11, GDF-8, and follistatin were not correlated cross-sectionally with the 3MSE or DSST, brain MRI findings of white matter hyperintensity, atrophy, or small infarcts, nor were they associated with incident dementia. FSTL-3 was modestly correlated with poorer cognitive function, greater white matter hyperintensities, and atrophy on MRI, as well as with incident dementia with an adjusted hazard ratio (HR) of 1.72 (95% CI = 1.13, 2.61) per doubling of FSTL-3. FSTL-3 was not associated with cognition or dementia in Health ABC, but GDF-8 was associated with both. The adjusted HR for incident dementia was 1.50 (95% CI = 1.07, 2.10) per doubling of GDF-8. CONCLUSIONS: Total GDF-11 level was not related to cognition or dementia in older adults. Associations of GDF-8 with cognitive outcomes in Health ABC were not expected, but consistent with animal models. Associations of FSTL-3 with cognition, brain abnormalities, and incident dementia in CHS implicate TGFβ superfamily inhibition in the pathogenesis of dementia.

Simple Summary: Activin is a dimeric growth factor with diverse biological activities in vertebrates. This study aimed to investigate the regulatory role of the activin signaling pathway in the ovary of cultured Acipenser sinensis. One activinβA subunit with a full-length cDNA sequence of 1572 base pairs was identified. Multiple sequence alignment and phylogenetic analyses indicated the conserved evolution of ActivinβA from mammals to fish species. Transcripts of activinβA were distributed ubiquitously in ovary and non-ovarian tissues. The in vitro human recombinant Activin A incubation stimulated not only the activin system-related gene transcriptions of activinβA, follistatin, its receptors activinRIIA and activinRIIB, and smad2, smad3, and smad4, but also the ovary development-related genes cyp19a1a, erα, and erβ. Gonadotropin activated activin signaling by recruiting activinβA, follistatin, activinRIIA, and smad2. These results were helpful for not only the molecular exploration of activin signaling in fish species, but also the ovarian maturation regulation of A. sinensis. Activin is a dimeric growth factor with diverse biological activities in vertebrates. This study aimed to investigate the regulatory role of the activin signaling pathway in the ovary of the endangered, cultured sturgeon species Acipenser sinensis. One activinβA subunit was identified, with a full-length complementary DNA (cDNA) sequence of 1572 base pairs. Multiple sequence alignment suggested that ActivinβA shared high sequence identities with its counterparts in four other sturgeon species. Phylogenetic analysis indicated the conserved evolution of ActivinβA among vertebrates from mammals to fish species. Transcripts of activinβA were distributed ubiquitously in the liver, kidney, intestine, ovary, midbrain, hypothalamus, and pituitary, with the highest transcription found in the pituitary. In Chinese sturgeon ovarian cells, in vitro human recombinant Activin A incubation stimulated the activin system-related gene transcriptions of activinβA, follistatin, its receptors -activinRIIA and activinRIIB, and drosophila mothers against decapentaplegic proteins (smads) smad2, smad3, and smad4. Ovary development-related mRNA levels of cyp19a1a and aromatase receptors of erα and erβ were enhanced by Activin A or human chorionic gonadotropin (hCG) incubation. Furthermore, 15 IU/mL hCG treatment increased the transcription levels of activinβA, follistatin, activinRIIA, and smad2. This suggested that the activin system was functional for the regulation of ovary development in Chinese sturgeon, possibly under the regulation of gonadotropin, by recruiting activinβA, follistatin, activinRIIA, and smad2. These results were helpful for the molecular exploration of activin signaling in fish species, as well as the ovarian maturation regulation of A. sinensis. [ABSTRACT FROM AUTHOR]

Clinical trials with treatments inhibiting myostatin pathways to increase muscle mass are currently ongoing in spinal muscular atrophy. Given evidence of potential myostatin pathway downregulation in Spinal Muscular Atrophy (SMA), restoring sufficient myostatin levels using disease-modifying treatments (DMTs) might arguably be necessary prior to considering myostatin inhibitors as an add-on treatment. This retrospective study assessed pre-treatment myostatin and follistatin levels' correlation with disease severity and explored their alteration by disease-modifying treatment in SMA. We retrospectively collected clinical characteristics, motor scores, and mysotatin and follistatin levels between 2018 and 2020 in 25 Belgian patients with SMA (SMA1 (n = 13), SMA2 (n = 6), SMA 3 (n = 6)) and treated by nusinersen. Data were collected prior to treatment and after 2, 6, 10, 18, and 30 months of treatment. Myostatin levels correlated with patients' age, weight, SMA type, and motor function before treatment initiation. After treatment, we observed correlations between myostatin levels and some motor function scores (i.e., MFM32, HFMSE, 6MWT), but no major effect of nusinersen on myostatin or follistatin levels over time. In conclusion, further research is needed to determine if DMTs can impact myostatin and follistatin levels in SMA, and how this could potentially influence patient selection for ongoing myostatin inhibitor trials. [ABSTRACT FROM AUTHOR]

Systemic lupus erythematosus (SLE) is an autoimmune and inflammatory disease with a risk associated with hormonal and reproductive factors. However, the potential causal effects between these factors and SLE remain unclear. A two-sample Mendelian randomization study was conducted using the published summary data from the genome-wide association study database. Five independent genetic variants associated with hormonal and reproductive factors were selected as instrumental variables: age at menarche, age at natural menopause, estradiol, testosterone, and follistatin. To estimate the causal relationship between these exposure factors and disease outcome, we employed the inverse-variance weighted, weighted median, and MR-Egger methods. In addition, we carried out multiple sensitivity analyses to validate model assumptions. Inverse variance weighted showed that there was a causal association between circulating follistatin and SLE risk (OR = 1.38, 95% CI 1.03 to 1.86, P = 0.033). However, no evidence was found that correlation between AAM (OR = 1.04, 95% CI 0.77 to 1.40, P = 0.798), ANM (OR = 0.99, 95% CI 0.92 to 1.06, P = 0.721), E2 (OR = 1.40, 95% CI 0.14 to 13.56, P = 0.772), T (OR = 1.25, 95% CI 0.70 to 2.28, P = 0.459), and SLE risk. Our study revealed that elevated circulating follistatin associates with an increased risk of SLE. This finding suggests that the regulatory signals mediated by circulating follistatin may provide a potential mechanism relevant to the treatment of SLE. [ABSTRACT FROM AUTHOR]

Background: Exercise-induced cytokines involved in controlling body composition include myostatin (MST) and follistatin (FST), both of which are influenced by physical activity. This study investigated changes in body composition and physical activity during a weight loss program, as well as the impact on serum MST and FST levels at various weight loss rates. Methods: A total of 126 patientswith obesitywho completed a 6-month weight loss program were divided into three groups based on weight loss rate (%): low (< 3%), middle (3-10%), and high (≥10%). The International Physical Activity Questionnaire was used for assessing physical activity, whereas dual X-ray absorptiometry was used to determine body composition. Serum MST and FST levels were measured using the enzyme-linked immunosorbent assay. Results: The middle and high groups showed a significant decrease in percent body fat and a significant increase in percent lean body mass and physical activity. Serum MST levels increased significantly in all three groups, although FST levels reduced significantly only in the middle group. After adjusting for sex and body composition, changes in peak oxygen intake (β = -0.359) and serum FST levels (β = -0.461) were identified as independent factors for the change in MST levels in the low group. Sex (β = -0.420) and changes in MST levels (β = -0.525) were identified as independent factors for the change in serum FST levels in the low group, whereas in the high group, sitting time (β = -0.600) during the weight loss program was identified as an independent factor for change in serum FST levels. Conclusion: Serum MST levels in patients with obesity increased significantly following the weight loss program, independent of weight loss rate. In contrast, serum FST levels reduced significantly only in the 3-10% weight loss group. These findings indicate that MST and FST secretion dynamics may fluctuate in response to physical activity, while also reflecting feedback regulation of body composition and metabolism during weight reduction. [ABSTRACT FROM AUTHOR]

The activins (A and B) and their binding protein, follistatin, play crucial roles in development, immunoregulation and inflammation throughout the body. In the male reproductive tract of the mouse, activin A and B production is largely confined to the initial segment and proximal caput of the epididymis and the efferent ducts, under normal conditions, with very low expression in the corpus, cauda and vas deferens. However, activin A protein is present throughout the epididymis and vas deferens and is largely associated with the epithelium and interstitial macrophages. Conversely, the activin‐binding protein follistatin is produced in the distal epididymis, with very high expression in the vas deferens. Activin activity in the distal tract is inhibited by follistatin, and the activin–follistatin balance is important for regulating coiling of the duct during epididymal development. In further experiments, as described in this report, in situ hybridisation was used to localise activin A mRNA principally to cells in the periductal zone and interstitium in the efferent ducts and proximal caput. Activin B mRNA, on the other hand, was localised to periductal cells in the efferent ducts and proximal epididymis and, most notably, to epithelial cells in the initial segment. Activin A is implicated in the regulation of mononuclear phagocyte function and immune responses in the caput and stimulates the expression of the key immunoregulatory protein, indoleamine 2,3‐dioxygenase in this region. Activin A production in the corpus and cauda increases dramatically during bacterial epididymitis in mice, promoting inflammation and fibrosis and causing damage to the epithelium and obstruction of the epididymal duct. Consequently, it appears that the activin–follistatin axis is crucial for maintaining normal epididymal structure and function, but disruption of this balance during inflammation has deleterious effects on male fertility. Follistatin has therapeutic potential in ameliorating the proinflammatory and profibrotic effects of activins. [ABSTRACT FROM AUTHOR]

Background and Purpose: Myostatin and follistatin are key proteins in muscle tissue regulation, growth, and hypertrophy. This study aimed to investigate the effects of two types of resistance training on the serum levels of myostatin and follistatin and the ratio of follistatin to myostatin in healthy young men. Materials and Methods: Twenty active young men were randomly divided into two equal groups of pyramid resistance exercises (, Mean±SD; age, 22.3±4.7 years; body mass index, 23.1±3.9 kg/m2 ; fat percentage, 27.6±10.7) and inverted pyramid resistance exercises (Mean±SD; age, 21.11±3.55 years; body mass index, 23.2±6.7 kg/m2 ; fat percentage, 26.3±13.8). The training lasted for eight weeks and three sessions per week. Each training session included six movements of chest press, leg press, barbell curl, triceps extensions, leg flexions, and leg extensions at an intensity corresponding to 100-50% of one maximum repetition in the pyramid resistance training group and at an intensity of 50-100% of one maximum repetition in the inverted pyramid resistance training group. Data analyses were carried out by using dependent t-test and ANCOVA at a significance level of P≤ 0.05. Results: Data analyses showed that eight weeks of pyramid and inverted pyramid resistance training caused a significant decrease in the serum level of myostatin (P=0.004,P=0.01, respectively) and a significant increase in the serum level of follistatin (p = 0.001, P=001), and the ratio of follistatin to myostatin (P=0.001, P=0.001) in healthy men. The results for ANCOVA analyses showed that there is no significant difference between the two groups for serum levels of myostatin, follistatin, and the ratio of follistatin to myostatin (p>0.05). Conclusion: Pyramid and reverse pyramid resistance training were associated with an increase in follistatin, the ratio of follistatin to myostatin, and a decrease in myostatin. Since, we found no significant difference between the experimental groups, it could be concluded that in young men these training protocols may lead to muscular hypertrophy similarly. [ABSTRACT FROM AUTHOR]

Metabolically healthy obesity (MHO) refers to obese individuals with a favorable metabolic profile, without severe metabolic abnormalities. This study aimed to investigate the potential of follistatin, a regulator of metabolic balance, as a biomarker to distinguish between metabolically healthy and unhealthy obesity. This cross-sectional study included 30 metabolically healthy and 32 metabolically unhealthy individuals with obesity. Blood samples were collected to measure the follistatin levels using an enzyme-linked immunosorbent assay (ELISA). While follistatin did not significantly differentiate between metabolically healthy (median 41.84 [IQR, 37.68 to 80.09]) and unhealthy (median 42.44 [IQR, 39.54 to 82.55]) individuals with obesity (p = 0.642), other biochemical markers, such as HDL cholesterol, triglycerides, C-peptide, and AST, showed significant differences between the two groups. Insulin was the most significant predictor of follistatin levels, with a coefficient of 0.903, followed by C-peptide, which exerted a negative influence at −0.624. Quantile regression analysis revealed nuanced associations between the follistatin levels and metabolic parameters in different quantiles. Although follistatin may not serve as a biomarker for identifying MHO and metabolically unhealthy obesity, understanding the underlying mechanisms that contribute to metabolic dysfunction could provide personalized strategies for managing obesity and preventing associated complications. [ABSTRACT FROM AUTHOR]

Background: Over 300 million individuals worldwide suffer from asthma. Furthermore, during the past three decades, western nations have demonstrated increased prevalence. 7.7% of people in Egypt's Nile Delta were found to have bronchial asthma. Follistatin-like 1 (FSTL1) may be crucial for the respiratory system, according to several studies. FSTL1 controls the maturation of alveoli, cartilage, and the development of the lungs. This study aimed to evaluate follistatin like protein 1 level in the serum of pediatric patients with asthma and determine its association to asthma severity. Methods: This case-control study was carried out on 60 children at pulmonology unit in pediatric department and clinical pathology department, Zagazig University Children Hospital in the period from May 2020 to June 2022. They were divided into group A: Consisted of 45 asthmatic children subdivided into 3 groups (mild -- moderate -- severe) and group B: consisted of 15 age and sex matched healthy children. Results: There was highly statistically significant increased FST level in severe group when compared with moderate group, mild group, and control group. Conclusion: In asthmatics, plasma FSTL1 levels were higher and positively correlated with severity of asthma. [ABSTRACT FROM AUTHOR]

Activin A is known to impede tubular repair following renal ischemia, whereas exogenous follistatin, an activin A antagonist, has been shown to ameliorate kidney damage in rats. Despite these findings, the precise role of endogenous follistatin in the kidney has yet to be elucidated. In this study, we investigated the localization of follistatin in the normal human kidney and its potential utility as a marker for acute kidney injury (AKI). In a total of 118 AKI patients and 16 healthy adults, follistatin levels in serum and urine were quantified using ELISA, and correlations with clinical parameters were analyzed. Follistatin-producing cells were positive for Na-Cl co-transporter and uromodulin, but negative for aquaporin 1 and aquaporin 2. Unlike healthy adults, urinary follistatin significantly increased in AKI patients, correlating positively with AKI severity. Urinary follistatin levels were notably higher in patients needing renal replacement therapy. Significant correlations were observed with urinary protein, α1 microglobulin, and urinary NGAL, but not with urinary KIM-1, urinary L-FABP, urinary NAG, urinary β2 microglobulin, or serum creatinine. Interestingly, no correlation between urinary and serum follistatin levels was identified, indicating a renal origin for urinary follistatin. In conclusion, follistatin, produced by distal tubules, is detectable in the urine of AKI patients, suggesting its potential as a valuable marker for monitoring acute tubular damage severity in AKI. [ABSTRACT FROM AUTHOR]

This study investigated the impact of the High Intensity Interval Resistance Training (HIIRT) protocol on hormonal changes in older women. Forty sarcopenic women were divided into an experimental group (EX = 30) and a control group (C = 10). The EX-group was further divided into Maintenance Training 1 (MT1 = 10), Maintenance Training 2 (MT2 = 10), and Detraining (DT = 10). The participants underwent 8 weeks of resistance training, consisting of hypertrophy and strength cycles. Following this, the EX-group had a 4-week period with no exercise or a reduced training volume. Measurements were taken at three time points. After 8 weeks, the EX-group showed significant improvements in Insulin Like Growth Factor-1 (IGF-1), Myostatin (MSTN), Follistatin (Fstn), Growth Hormone (GH) and Cortisol (Cort) compared to the control group. During the volume reduction period, there were no significant differences between MT1 and MT2 groups, but both groups saw increases in IGF-1, Fstn, GH, and decreases in MSTN and Cort compared to the DT group. These findings suggest that performing at least one training session per week with the HIIRT protocol is crucial for maintaining hormonal adaptations in sarcopenic older women. [ABSTRACT FROM AUTHOR]

Recombinant human follistatin (rhFST) is a potential performance‐enhancing agent owing to its stimulating effect on muscle growth. Administration of rhFST to athletes is prohibited in human sports by the World Anti‐Doping Agency (WADA) and in horseracing according to Article 6 of the International Agreement on Breeding, Racing and Wagering published by the International Federation of Horseracing Authorities (IFHA). For effective control of the potential misuse of rhFST in flat racing, methods for screening and confirmatory analysis are required. This paper describes the development and validation of a complete solution for detecting rhFST and confirming its presence in plasma samples collected from racehorses. A high‐throughput analysis of rhFST with a commercially available enzyme‐linked immunosorbent assay (ELISA) was evaluated for the screening of equine plasma samples. Any suspicious finding would then be subjected to a confirmatory analysis using immunocapture, followed by nano‐liquid chromatography/high‐resolution tandem mass spectrometry (nanoLC‐MS/HRMS). The confirmation of rhFST by nanoLC‐MS/HRMS was achieved by comparing the retention times and relative abundances of three characteristic product‐ions with those from the reference standard in accordance with the industry criteria published by the Association of Official Racing Chemists. The two methods achieved comparable limit of detection (~2.5–5 ng/mL) and limit of confirmation (2.5 ng/mL or below), as well as adequate specificity, precision and reproducibility. To our knowledge, this is the first report of the screening and confirmation methods for rhFST in equine samples. [ABSTRACT FROM AUTHOR]

Objectives: The link between aging and pulmonary function decline is well-established, but the underlying mechanisms have yet to be fully revealed. Serum follistatin, a myokine implicated in muscle degeneration, may play a role in age-related pulmonary changes. This study aims to investigate the relationship between serum follistatin levels and pulmonary function decline in community-dwelling older adults, and evaluate their combined association with all-cause mortality. Research design and methods: This longitudinal cohort study utilized data from 751 participants aged ≥50 years in the I-Lan Longitudinal Aging Study between 2018−2019. Serum follistatin levels, spirometry results, demographic and clinical data were retrieved. Participants were stratified based on their follistatin levels. Survival curves and group comparisons based on follistatin levels and decline in peak expiratory flow (PEF) using Kaplan-Meier analysis and log-rank tests. Multivariate Cox proportional hazards models were further used to identify independent predictors of all-cause mortality during the 52-month follow-up. Results: Elevated follistatin levels significantly correlated with worse pulmonary function, particularly decreased PEF (p = 0.030). Kaplan–Meier analysis revealed the combination of elevated follistatin levels and decreased PEF was associated with increased risk of all-cause mortality (Log-rank p = 0.023). Cox proportional hazards models further identified that concurrent presence of higher follistatin levels and decreased PEF predicted higher risk of all-cause mortality (adjusted HR 3.58, 95% CI: 1.22–10.53, p = 0.020). Conclusion: Higher serum follistatin levels correlate with decreased pulmonary function, specifically PEF decline, in community-dwelling older adults. Furthermore, the coexistence of elevated follistatin levels and decreased PEF was associated with risk of all-cause mortality. Follistatin may serve as a biomarker for pulmonary aging and related adverse outcomes.

Simple Summary: Within the extracellular milieu surrounding cancer cells exists an ecosystem of heterogeneous cell populations that dictate tumor growth and survival via cell–cell signaling induced by secreted factors. The transforming growth factor-β (TGF-β) superfamily, a crucial programmer of the tumor microenvironment, presents challenges as a therapeutic target due to its biphasic effects in cancer. Despite concerted efforts, the clinical efficacy of its antagonists remains elusive, reflecting a limited understanding of how cancer cells can become nonresponsive to the potent cytostatic effects of these ligands while retaining their tumor promoting effects. Follistatin, a secreted glycoprotein and an endogenous bioneutralizer of TGF-β ligands, has gained prominence and emerged as a potentially targetable modulator of key resident cell populations in the tumor microenvironment, particularly in squamous cell carcinoma. We delve deeper into the expression patterns and mechanistic role of follistatin in cancer, examining its intimate relationship with TGF-β and its implications in drug resistance across lung, ovarian, and head and neck cancers. Follistatin (FST) is a potent neutralizer of the transforming growth factor-β superfamily and is associated with normal cellular programs and various hallmarks of cancer, such as proliferation, migration, angiogenesis, and immune evasion. The aberrant expression of FST by solid tumors is a well-documented observation, yet how FST influences tumor progression and therapy response remains unclear. The recent surge in omics data has revealed new insights into the molecular foundation underpinning tumor heterogeneity and its microenvironment, offering novel precision medicine-based opportunities to combat cancer. In this review, we discuss these recent FST-centric studies, thereby offering an updated perspective on the protean role of FST isoforms in shaping the complex cellular ecosystem of tumors and in mediating drug resistance. [ABSTRACT FROM AUTHOR]

Previous study showed that elevated circulating hepatokine follistatin (FST) associates with an increased risk of type 2 diabetes by inducing adipose tissue insulin resistance. Here we explore further the relationships between plasma FST levels with mortality and health outcomes. The population-based Malmö Diet Cancer cardiovascular cohort (n = 4733, age 45–68 years) was used to study plasma FST in relation to incidence of health outcomes, by linkage with national patient registers. Cox regression analysis was used to assess the associations of plasma FST and outcomes, with adjustments for multiple potential confounding factors. During the mean follow-up time of 22.64 ± 5.84 years in 4,733 individuals, 526 had incident stroke, 432 had ischemic stroke, 530 had incident coronary events (CE), 339 had incident heart failure (HF), 320 had incident chronic kidney disease (CKD) and 1,843 individuals died. Hazard ratio (HR) per standard deviation increase in FST levels adjusted for multiple risk factors was 1.05 (95%CI: 1.00–1.11, p = 0.036) for mortality; 1.10 (95%CI: 1.00–1.20, p = 0.042) for stroke; 1.13 (95%CI: 1.03–1.25, p = 0.014) for ischemic stroke; 1.16 (95%CI: 1.03–1.30, p = 0.015) for HF; and 1.38 (95%CI: 1.12–1.70, p = 0.003) for a diagnosis of CKD. In MDC-CC individuals without prevalent or incident diabetes, the association between FST and stroke, CE and CKD remained significant; but not with mortality or HF. Elevated circulating FST associates with an increased risk of mortality and HF, which partly may be mediated by diabetes. FST also associated with stroke, ischemic stroke, CE and CKD, independently of established risk factors including diabetes. • Elevated circulating follistatin associates with an increased risk of mortality and heart failure. • The association between follistatin and increased risk of mortality and heart failure is partly mediated by diabetes. • Follistatin associates with stroke, incident coronary events and chronic kidney disease, independently of diabetes. [ABSTRACT FROM AUTHOR]

Background: Recurrent pregnancy loss is a distressing event during pregnancy, and understanding its causal factors is crucial. Follistatin, a glycoprotein involved in folliculogenesis and embryogenesis, has been implicated as a potential contributor to the risk of spontaneous abortion. However, establishing a causal relationship requires rigorous investigation using robust methods. Methods: In this study, we utilized mendelian randomization (MR), a powerful genetic epidemiological approach, to examine the causal relationship between follistatin levels and spontaneous abortion. We obtained instrumental variables strongly associated with follistatin levels from largescale genome-wide association from the IEU database. The inverse variance weighting (IVW) method was taken as gold standard. We also performed sensitivity test to evaluate the robustness of our result. Results: MR analysis revealed a significant causal relationship between low follistatin levels and spontaneous abortion (p = 0.03). Sensitivity analyses, including pleiotropy test, heterogeneity test, and leave-one-out analysis, all supported the robustness of our findings. Conclusion: Our study provides compelling evidence supporting the causal relationship between low follistatin levels and increased risk of spontaneous abortion. These findings underscore the importance of follistatin in the etiology of spontaneous abortion and suggest potential preventive interventions. Modulating follistatin levels or relevant pathways could hold promise for reducing the incidence of spontaneous abortion and improving reproductive outcomes. The utilization of MRs strengthens the validity of our results by mitigating confounding and reverse causality biases. Further research is needed to elucidate the underlying molecular mechanisms and explore therapeutic strategies targeting follistatin levels. [ABSTRACT FROM AUTHOR]

Background Heterochronic parabiosis has identified growth differentiation factor (GDF)-11 as a potential means of cardiac rejuvenation, but findings have been inconsistent. A major barrier has been lack of assay specificity for GDF-11 and its homolog GDF-8. Methods We tested the hypothesis that GDF-11 and GDF-8, and their major antagonists follistatin and follistatin-like (FSTL)-3, are associated with incident heart failure (HF) and its subtypes in elders. Based on validation experiments, we used liquid chromatography–tandem mass spectrometry to measure total serum GDF-11 and GDF-8, along with follistatin and FSTL-3 by immunoassay, in 2 longitudinal cohorts of older adults. Results In 2 599 participants (age 75.2 ± 4.3) followed for 10.8 ± 5.6 years, 721 HF events occurred. After adjustment, neither GDF-11 (HR per doubling: 0.93 [0.67, 1.30]) nor GDF-8 (HR: 1.02 per doubling [0.83, 1.27]) was associated with incident HF or its subtypes. Positive associations with HF were detected for follistatin (HR: 1.15 [1.00, 1.32]) and FLST-3 (HR: 1.38 [1.03, 1.85]), and with HF with preserved ejection fraction for FSTL-3 (HR: 1.77 [1.03, 3.02]). (All HRs per doubling of biomarker.) FSTL-3 associations with HF appeared stronger at higher follistatin levels and vice versa, and also for men, Blacks, and lower kidney function. Conclusions Among older adults, serum follistatin and FSTL-3, but not GDF-11 or GDF-8, were associated with incident HF. These findings do not support the concept that low serum levels of total GDF-11 or GDF-8 contribute to HF late in life, but do implicate transforming growth factor-β superfamily pathways as potential therapeutic targets. [ABSTRACT FROM AUTHOR]

Background and Purpose: Irisin is an exercise-stimulated hormone that affects white adipose tissue and brown adipose tissue. Based on the previous studies, physical activity increases the expression of proteins such as follistatin, which causes weight loss by increasing energy expenditure and through this has an effect on the insulin resistance index. The present study aimed to investigate the response of plasma levels of irisin, follistatin, and insulin resistance index to two types of high-intensity interval training (HIIT) in overweight men. Materials and Methods: For this purpose, 33 overweight men (mean age 22.9±2.11 years, weight 82.45±6.1 kg, body mass index 26.7±1.22 kg/m²) who were able to regularly attend physical activity voluntarily participated in the study and were randomly divided into three groups: 30-s HIIT groups (HIIT-30), 60-s HIIT (HIIT-60), and control. The training protocol was performed three sessions per week for eight weeks. The HIIT-30 exercise program included eight repetitions of 30-second activity at an intensity of 80-90% of the maximum heart rate with a two-minute recovery for the first four weeks, ten repetitions for the fifth and sixth weeks, and twelve repetitions for the seventh and eighth weeks. The HIIT-60 exercise program included four repetitions of 60-second activity at an intensity of 80-90% of the maximum heart rate with a four-minute recovery for the first four weeks, five repetitions for the fifth and sixth weeks, and six repetitions for the seventh and eighth weeks. The control group did not attend any regular exercise program during the research. Blood samples were taken to measure levels of Irisin, follistatin, and determine the insulin resistance index. One-way analysis of variance (ANOVA) and paired t-test were utilized at a level of P≤0.05 to compare means of parameters. Results: The within-group comparisons for irisin and follistatin data showed that there is a significant difference between pre-test and post-test in the 30-s HIIT and 60-s HIIT groups (P<0.05). The results of ANOVA indicated that the 30-s HIIT and 60-s HIIT protocols increased the levels of irisin (P<0.05), follistatin (P<0.05), and reduced insulin resistance index significantly (P<0.05). The between-group comparisons of the data showed no significant differences between the HIIT-30 group and the HIIT-60 group for all variables. Conclusion: According to the results of this research, it could be concluded that, the two HIIT methods of 30 and 60 seconds by increasing irisin and follistatin levels can cause weight loss, treat obesity and improve the insulin resistance index in overweight men. [ABSTRACT FROM AUTHOR]

Background: Biological aging is a physiological process that can be altered by various factors. The presence of a chronic metabolic disease can accelerate aging and increase the risk of further chronic diseases. The aim of the study was to determine whether the presence of metabolic syndrome (MetS) affects levels of markers that are associated with, among other things, aging. Material and Methods: A total of 169 subjects (58 with MetS, and 111 without metabolic syndrome, i.e., non-MetS) participated in the study. Levels of telomerase, GDF11/15, sirtuin 1, follistatin, NLRP3, AGEs, klotho, DNA/RNA damage, NAD+, vitamin D, and blood lipids were assessed from blood samples using specific enzyme-linked immunosorbent assay (ELISA) kits. Results: Telomerase (p < 0.01), DNA/RNA damage (p < 0.006) and GDF15 (p < 0.02) were higher in MetS group compared to non-MetS group. Only vitamin D levels were higher in the non-MetS group (p < 0.0002). Differences between MetS and non-MetS persons were also detected in groups divided according to age: in under 35-year-olds and those aged 35–50 years. Conclusions: Our results show that people with MetS compared to those without MetS have higher levels of some of the measured markers of biological aging. Thus, the presence of MetS may accelerate biological aging, which may be associated with an increased risk of chronic comorbidities that accompany MetS (cardiovascular, inflammatory, autoimmune, neurodegenerative, metabolic, or cancer diseases) and risk of premature death from all causes. [ABSTRACT FROM AUTHOR]

Aims Numerous studies have established that resistance training is highly effective in preventing and addressing age-related muscle loss (sarcopenia) by enhancing the physiological function of skeletal muscle tissue. Thus, the objective of this study was to assess the impact of 12 weeks of incremental resistance training on the serum levels of myostatin, follistatin, and insulin-like growth factor-1 (IGF-I) in sedentary elderly men. Materials & Methods Thirty sedentary elderly men voluntarily participated in this semiexperimental study and were randomly assigned to either a control group (15 men) with an average age of 62.1±3.7 years and weight of 85.1±7.7 kg, or a resistance training group (15 men) with an average age of 61.3±1.6 years and weight of 82.3±7.8 kg. The resistance training group undertook a 12-week training protocol, while the control group did not engage in any training program during this time. Blood samples and body composition measurements (using dual X-ray absorptiometry) were taken before the study commenced and 48 hours after the last training session concluded. Serum levels of myostatin, follistatin, and IGF-I were determined using the ELISA method. An independent t-test was employed to establish statistical significance between the groups, utilizing SPSS 21 software. Findings After 12 weeks of resistance training, there was a significant decrease in serum myostatin levels and significant increases in serum follistatin and IGF-I levels in comparison to the control group (p=0.05). Conclusion Incremental resistance training proves to be an effective intervention for preventing sarcopenia in elderly individuals by decreasing serum levels of myostatin and increasing serum levels of follistatin and IGF-I. [ABSTRACT FROM AUTHOR]

Follistatin (FST), a member of the transforming growth factor‐β (TGF‐β) superfamily, has been identified as an inhibitor of follicle‐stimulating hormone. Previous studies showed that it plays an important role in animal reproduction. Therefore, this study aims to investigate its effect on the maturation of buffalo oocytes in vitro, and the underlying mechanism of FST affecting oocyte maturation was also explored in buffalo cumulus cells. Results showed that FST was enriched in the ovary and expressed at different stages of buffalo ovarian follicles as well as during oocyte maturation and early embryo development. The FST expression level was up‐regulated in MII buffalo oocytes compared with the GV stage (p <.05). To study the effects of FST on buffalo oocytes' maturation and early embryonic development, we added the pcD3.1 skeleton vector and PCD3.1‐EGFP‐FST vector into the maturation fluid of buffalo oocytes, respectively. It was demonstrated that FST promoted the in vitro maturation rate of buffalo oocytes and the blastocyst rate of embryos cultured in vitro (p <.05). By interfering with FST expression, we discovered that FST in cumulus cells plays a crucial role in oocyte maturation. Interference with the FST expression during the buffalo oocyte maturation did not affect the first polar body rate of buffalo oocyte (p >.05). In contrast, the location of mitochondria in oocytes was abnormal, and the cumulus expansion area was reduced (p <.05). After parthenogenetic activation, the cleavage and blastocyst rates of the FST‐interfered group were reduced (p <.05). Furthermore, RT‐qPCR was performed to investigate further the underlying mechanism by which FST enhances oocyte maturation. We found that overexpression of FST could up‐regulate the expression level of apoptosis suppressor gene Bcl‐2 and TGF‐β/SMAD pathway‐related genes TGF‐β, SMAD2, and SMAD3 (p <.05). In contrast, the expression levels of SMAD4 and pro‐apoptotic gene BAX were significantly decreased (p <.05). The FST gene could affect buffalo oocyte maturation by regulating the oocyte mitochondria integrity, the cumulus expansion, cumulus cell apoptosis, and the expression levels of TGF‐β/SMAD pathway‐related genes. [ABSTRACT FROM AUTHOR]

The biological mechanisms underpinning learning are unclear. Mounting evidence has suggested that adult hippocampal neurogenesis is involved although a causal relationship has not been well defined. Here, using high-resolution genetic mapping of adult neurogenesis, combined with sequencing information, we identify follistatin (Fst) and demonstrate its involvement in learning and adult neurogenesis. We confirmed that brain-specific Fst knockout (KO) mice exhibited decreased hippocampal neurogenesis and demonstrated that FST is critical for learning. Fst KO mice exhibit deficits in spatial learning, working memory, and long-term potentiation (LTP). In contrast, hippocampal overexpression of Fst in KO mice reversed these impairments. By utilizing RNA sequencing and chromatin immunoprecipitation, we identified Asic4 as a target gene regulated by FST and show that Asic4 plays a critical role in learning deficits caused by Fst deletion. Long-term overexpression of hippocampal Fst in C57BL/6 wild-type mice alleviates age-related decline in cognition, neurogenesis, and LTP. Collectively, our study reveals the functions for FST in adult neurogenesis and learning behaviors.

Follistatin (FST)/myostatin (MST) myokine-signaling axis is important for muscle metabolism and pathogenesis of obesity. FST, mainly secreted by skeletal muscle and liver, inhibits MST and affects skeletal muscle synthesis. This study aimed to identify the characteristics of myokines and independent predictors of serum FST levels in patients with obesity. In this retrospective cross-sectional study, 226 patients (mean age, 46.6 years; men, 35.4%) with obesity who initially visited an outpatient clinic between June 2014 and September 2020, were included and classified into obesity (25.0 ≤ body mass index (BMI) < 35.0 kg/m2) and severe obesity (BMI ≥35 kg/m2) groups based on the guidelines of the Japan Society for the Study of Obesity. Body composition was measured using bioelectrical impedance analysis and computed tomography. Muscle strength, exercise tolerance, metabolic parameters, and myokines were measured, including serum levels of FST, MST, irisin, and brain-derived neurotrophic factor. Serum FST levels were significantly higher in the severe obesity group than in the obesity group (median: 768.4 vs. 895.1 pg/mL, P = 0.020). However, the levels of other myokines showed no significant differences between the groups. In Model 1, which included factors that significantly correlated with FST levels, stepwise multivariate regression analysis revealed peak oxygen uptake (VO2) as an independent predictor of FST levels based on the significance of the univariate analysis. Additionally, Model 2 was analyzed by adding myokine level to Model 1, revealing that peak VO2, MST, and irisin levels were independent predictors of FST levels. Serum FST levels were higher in patients in the severe obesity group compared to those in the obesity group. There was an independent association between low exercise tolerance and elevated serum FST levels. [ABSTRACT FROM AUTHOR]

Aim: Skeletal muscle is the largest tissue that regulates metabolic homeostasis with metabolic communication caused by various myokines. Therefore, in this research, the effect of 8 weeks of HIIT exercises on the serum levels of myostatin and follistatin in inactive obese young women. Method: The current semi-experimental research was conducted with two training and control groups on 30 inactive young women in the age range of (33.12±1.41) years and average height (160.21±4.1) cm. became. The training group performed HIIT exercises for 8 weeks, and three sessions per week with an intensity of 70-85% of the reserve heart rate, and during this period, the control group did not do any physical activity. Blood samples were taken 48 hours before and after exercise intervention in order to measure myostatin and follistatin variables. Data analysis was done by covariance analysis using 22spss software at a significance level of 5%. Result: The results of this research showed that the serum level of myostatin after 8 weeks of HIIT exercises in the training group (681.87±7.9) compared to the control group (882.76±7.3) had a significant decrease (p 0.001). <) while the follistatin serum level in the training group (41.21±2.6) compared to the control group (35.98±8.9) after the test showed a significant increase (p<0.001). Conclusion: Performing HIIT exercises can decrease the serum level of myostatin and increase the serum level of follistatin in human samples and can lead to muscle hypertrophy. [ABSTRACT FROM AUTHOR]

Background and Objectives Recently, performing regular sports activities has been considered an effective strategy for the rehabilitation of patients who have recovered from COVID-19. The present study aimed to assess the effect of eight weeks of selected aerobic and resistance exercises on the plasma levels of irisin, follistatin, and fibroblast growth factor 21 (FGF21) in women who recovered from COVID-19. Subjects and Methods A total of 33 women who recovered from COVID-19 were assigned to three groups, namely aerobic exercise, resistance, and control, after the general call and selection. Aerobic training with an intensity of 50%-70% of the reserve heart rate and resistance training with an intensity of 40%-75% of a maximum repetition was performed for eight weeks (three sessions per week). Irisin, follistatin, and FGF21 levels were measured using the ELISA method. The data were analyzed using the analysis of variance statistical test at the significant level of < 0.05. Results As illustrated by the results, selected aerobic and resistance exercises caused a significant increase in irisin, follistatin, and FGF21 levels. The results of the post hoc test demonstrated that this increase was significant in the aerobic and resistance groups compared to the control group. Moreover, within-group changes pointed to a significant increase in the mean before and after the intervention in the aerobic and resistance groups. Conclusion Carrying out selected aerobic and resistance exercises in women who recovered from COVID-19 boosts their physical strength and is effective in quick recovery by restoring some indicators of myokine profile. [ABSTRACT FROM AUTHOR]

Purpose: The activins-follistatins-inhibins (AFI) hormonal system is considered to regulate muscle and bone mass. We aimed to evaluate AFI in postmenopausal women with an incident hip fracture. Methods: In this post-hoc analysis of a hospital based case-control study, we evaluated circulating levels of the AFI system in postmenopausal women with a low-energy hip fracture admitted for fixation compared with postmenopausal women with osteoarthritis scheduled for arthroplasty. Results: Circulating levels of follistatin (p = 0.008), FSTL3 (p = 0.013), activin B and AB (both p < 0.001), as well as activin AB/follistatin and activin AB/FSTL3 ratios (p = 0.008 and p = 0.029, respectively) were higher in patients than controls in unadjusted models. Differences for activins B and AB remained after adjustment for age and BMI (p = 0.006 and p = 0.009, respectively) and for FRAX-based risk for hip fracture (p = 0.008 and p = 0.012, respectively) but were lost when 25OHD was added to the regression models. Conclusions: Our data indicate no major changes in the AFI system in postmenopausal women at the time of hip fracture compared to postmenopausal women with osteoarthritis except for higher activin B and AB levels, whose significance, however, was lost when 25OHD was added to the adjustment models. Clinical Trials: Clinical Trials identifier: NCT04206618. [ABSTRACT FROM AUTHOR]

This study aimed to investigate the effect of quercetin supplementation and training on myostatin and follistatin levels in the heart tissue of diabetic rats. Methods: For this purpose, 50 10-week-old male Wistar rats with an average weight of 237±33 grams were randomly divided into five groups of 10 including: healthy control, diabetes, diabetes+supplement, diabetes+exercise, and diabetes+supplement+exercise.The training protocol includes five sessions per week for eight weeks on a treadmill without a special slope. The rodents ran for 60 minutes at a speed of 25 meters per minute in each session.and the supplement groups received 50 mg/kg quercetin daily by gavage. The results showed that the difference in myostatin levels among the groups is significant (P=0.001). There was a significant decrease in myostatin levels between exercise+supplement+diabetes group with diabetes (P=0.002) There was also a significant difference between the supplement+diabetes and exercise+diabetes groups (P=0.009). Also, the results showed that the difference in follistatin levels among the groups is significant (P=0.001). The results showed that follistatin levels in the heart tissue increased significantly between the groups of diabetes, exercise+diabetes,supplement+diabetes and exercise+supplements+diabetes with the control group (respectively: P=0.005; P=0.001; P=0.001; P = 0.001).It seems that moderate intensity aerobic exercise and quercetin supplementation have a positive and beneficial effect on the levels of myostatin and folstatin. [ABSTRACT FROM AUTHOR]

Inflammatory bowel disease (IBD) is an immune-mediated inflammatory condition predominantly affecting the gastrointestinal (GI) tract. An increasing prevalence of IBD has been observed globally. The pathogenesis of IBD includes a complex interplay between the intestinal microbiome, diet, genetic factors and immune responses. The consequent imbalance of inflammatory mediators ultimately leads to intestinal mucosal damage and defective repair. Growth factors, given their specific roles in maintaining the homeostasis and integrity of the intestinal epithelium, are of particular interest in the setting of IBD. Furthermore, direct targeting of growth factor signalling pathways involved in the regeneration of the damaged epithelium and the regulation of inflammation could be considered as therapeutic options for individuals with IBD. Several members of the transforming growth factor (TGF)-β superfamily, particularly TGF-β, activin and follistatin, are key candidates as they exhibit various roles in inflammatory processes and contribute to maintenance and homeostasis in the GI tract. This article aimed firstly to review the events involved in the pathogenesis of IBD with particular emphasis on TGF-β, activin and follistatin and secondly to outline the potential role of therapeutic manipulation of these pathways.

Reciprocal interactions between prostate cancer cells and carcinoma‐associated fibroblasts (CAFs) mediate cancer development and progression; however, our understanding of the signalling pathways mediating these cellular interactions remains incomplete. To address this, we defined secretome changes upon co‐culture of prostate epithelial or cancer cells with fibroblasts that mimic bi‐directional communication in tumours. Using antibody arrays, we profiled conditioned media from mono‐ and co‐cultures of prostate fibroblasts, epithelial and cancer cells, identifying secreted proteins that are upregulated in co‐culture compared to mono‐culture. Six of these (CXCL10, CXCL16, CXCL6, FST, PDGFAA, IL‐17B) were functionally screened by siRNA knockdown in prostate cancer cell/fibroblast co‐cultures, revealing a key role for follistatin (FST), a secreted glycoprotein that binds and bioneutralises specific members of the TGF‐β superfamily, including activin A. Expression of FST by both cell types was required for the fibroblasts to enhance prostate cancer cell proliferation and migration, whereas FST knockdown in co‐culture grafts decreased tumour growth in mouse xenografts. This study highlights the complexity of prostate cancer cell–fibroblast communication, demonstrates that co‐culture secretomes cannot be predicted from individual cultures, and identifies FST as a tumour‐microenvironment‐derived secreted factor that represents a candidate therapeutic target.

INTRODUCTION: We conducted an open-label study to examine the effects of the flavonoid (-)-epicatechin in seven ambulatory adult patients with Becker muscular dystrophy (BMD). METHODS: Seven participants received (-)-epicatechin 50 mg twice per day for 8 weeks. Pre- and postprocedures included biceps brachii biopsy to assess muscle structure and growth-relevant endpoints by western blotting, mitochondria volume measurement, and cristae abundance by electron microscopy, graded exercise testing, and muscle strength and function tests. RESULTS: Western blotting showed significantly increased levels of enzymes modulating cellular bioenergetics (liver kinase B1 and 5-adenosine monophosphate-activated protein kinase). Peroxisome proliferator-activated receptor gamma coactivator-1alpha, a transcriptional coactivator of genes involved in mitochondrial biogenesis and cristae-associated mitofilin levels, increased as did cristae abundance. Muscle and plasma follistatin increased significantly while myostatin decreased. Markers of skeletal muscle regeneration myogenin, myogenic regulatory factor-5, myoblast determination protein 1, myocyte enhancer factor-2, and structure-associated proteins, including dysferlin, utrophin, and intracellular creatine kinase, also increased. Exercise testing demonstrated decreased heart rate, maximal oxygen consumption per kilogram, and plasma lactate levels at defined workloads. Tissue saturation index improved in resting and postexercise states. DISCUSSION: (-)-Epicatechin, an exercise mimetic, appears to have short-term positive effects on tissue biomarkers indicative of mitochondrial biogenesis and muscle regeneration, and produced improvements in graded exercise testing parameters in patients with BMD.

Heparin and heparan sulfate (HS) are highly sulfated polysaccharides covalently bound to cell surface proteins, which directly interact with many extracellular proteins, including the transforming growth factor-β (TGFβ) family ligand antagonist, follistatin 288 (FS288). Follistatin neutralizes the TGFβ ligands, myostatin and activin A, by forming a nearly irreversible non-signaling complex by surrounding the ligand and preventing interaction with TGFβ receptors. The FS288-ligand complex has higher affinity than unbound FS288 for heparin/HS, which accelerates ligand internalization and lysosomal degradation; however, limited information is available for how FS288 interactions with heparin affect ligand binding. Using surface plasmon resonance (SPR) we show that preincubation of FS288 with heparin/HS significantly decreased the association kinetics for both myostatin and activin A with seemingly no effect on the dissociation rate. This observation is dependent on the heparin/HS chain length where small chain lengths less than degree of polymerization 10 (dp10) did not alter association rates but chain lengths >dp10 decreased association rates. In an attempt to understand the mechanism for this observation, we uncovered that heparin induced dimerization of follistatin. Consistent with our SPR results, we found that dimerization only occurs with heparin molecules >dp10. Small-angle X-ray scattering of the FS288 heparin complex supports that FS288 adopts a dimeric configuration that is similar to the FS288 dimer in the ligand-bound state. These results indicate that heparin mediates dimerization of FS288 in a chain-length-dependent manner that reduces the ligand association rate, but not the dissociation rate or antagonistic activity of FS288.

Obesity is a global health problem and a major risk factor for several metabolic conditions including dyslipidemia, diabetes, insulin resistance and cardiovascular diseases. Obesity develops from chronic imbalance between energy intake and energy expenditure. Stimulation of cellular energy burning process has the potential to dissipate excess calories in the form of heat via the activation of uncoupling protein-1 (UCP1) in white and brown adipose tissues. Recent studies have shown that activation of transforming growth factor-β (TGF-β) signaling pathway significantly contributes to the development of obesity, and blockade or inhibition is reported to protect from obesity by promoting white adipose browning and increasing mitochondrial biogenesis. Identification of novel compounds that activate beige/brown adipose characteristics to burn surplus calories and reduce excess storage of fat are actively sought in the fight against obesity. In this review, we present recent developments in our understanding of key modulators of TGF-β signaling pathways including follistatin (FST) and myostatin (MST) in regulating adipose browning and brown adipose mass and activity. While MST is a key ligand for TGF-β family, FST can bind and regulate biological activity of several TGF-β superfamily members including activins, bone morphogenic proteins (BMP) and inhibins. Here, we review the literature supporting the critical roles for FST, MST and other proteins in modulating TGF-β signaling to influence beige and brown adipose characteristics. We further review the potential therapeutic utility of FST for the treatment of obesity and related metabolic disorders.

Activin A is known to impede tubular repair following renal ischemia, whereas exogenous follistatin, an activin A antagonist, has been shown to ameliorate kidney damage in rats. Despite these findings, the precise role of endogenous follistatin in the kidney has yet to be elucidated. In this study, we investigated the localization of follistatin in the normal human kidney and its potential utility as a marker for acute kidney injury (AKI). In a total of 118 AKI patients and 16 healthy adults, follistatin levels in serum and urine were quantified using ELISA, and correlations with clinical parameters were analyzed. Follistatin-producing cells were positive for Na-Cl co-transporter and uromodulin, but negative for aquaporin 1 and aquaporin 2. Unlike healthy adults, urinary follistatin significantly increased in AKI patients, correlating positively with AKI severity. Urinary follistatin levels were notably higher in patients needing renal replacement therapy. Significant correlations were observed with urinary protein, α1 microglobulin, and urinary NGAL, but not with urinary KIM-1, urinary L-FABP, urinary NAG, urinary β2 microglobulin, or serum creatinine. Interestingly, no correlation between urinary and serum follistatin levels was identified, indicating a renal origin for urinary follistatin. In conclusion, follistatin, produced by distal tubules, is detectable in the urine of AKI patients, suggesting its potential as a valuable marker for monitoring acute tubular damage severity in AKI.

Follistatin is a member of the activin–follistatin–inhibin hormonal system and is proposed to affect bone metabolism. However, data regarding the effect of follistatin on bone are relatively scarce and contradictory in humans. The purpose of the current study was to investigate possible associations of serum follistatin concentration with bone mineral characteristics in lean and physically active adolescent girls. Bone mineral density, body composition, resting energy expenditure and different energy homeostasis hormones in serum including follistatin, leptin and insulin were investigated. Significant relationships (p < 0.05) between serum follistatin (1275.1 ± 263.1 pg/mL) and whole-body (WB) bone mineral content (r = 0.33), WB areal bone mineral density (aBMD) (r = 0.23) and lumbar spine (LS) aBMD (r = 0.29) values were observed. Serum follistatin remained associated with LS aBMD independent of body fat and lean masses (r = 0.21; p < 0.05). However, the follistatin concentration explained only 3% (R2 × 100; p = 0.049) of the total variance in LS aBMD values. In conclusion, serum follistatin concentrations were associated with bone mineral values in lean adolescent girls with increased physical activity. Follistatin was an independent predictor of lumbar spine areal bone mineral density, which predominantly consists of trabecular bone. [ABSTRACT FROM AUTHOR]

How left-right (LR) asymmetry emerges in a patterning field along the anterior-posterior axis remains an unresolved problem in developmental biology. Left-biased Nodal emanating from the LR organizer propagates from posterior to anterior (PA) and establishes the LR pattern of the whole embryo. However, little is known about the regulatory mechanism of the PA spread of Nodal and its asymmetric activation in the forebrain. Here, we identify bilaterally expressed Follistatin (Fst) as a regulator blocking the propagation of the zebrafish Nodal ortholog Southpaw (Spaw) in the right lateral plate mesoderm (LPM), and restricting Spaw transmission in the left LPM to facilitate the establishment of a robust LR asymmetric Nodal patterning. In addition, Fst inhibits the Activin-Nodal signaling pathway in the forebrain thus preventing Nodal activation prior to the arrival, at a later time, of Spaw emanating from the left LPM. This contributes to the orderly propagation of asymmetric Nodal activation along the PA axis. The LR regulation function of Fst is further confirmed in chick and frog embryos. Overall, our results suggest that a robust LR patterning emerges by counteracting a Fst barrier formed along the PA axis. [ABSTRACT FROM AUTHOR]

Inflammatory bowel disease (IBD) is an immune-mediated inflammatory condition predominantly affecting the gastrointestinal (GI) tract. An increasing prevalence of IBD has been observed globally. The pathogenesis of IBD includes a complex interplay between the intestinal microbiome, diet, genetic factors and immune responses. The consequent imbalance of inflammatory mediators ultimately leads to intestinal mucosal damage and defective repair. Growth factors, given their specific roles in maintaining the homeostasis and integrity of the intestinal epithelium, are of particular interest in the setting of IBD. Furthermore, direct targeting of growth factor signalling pathways involved in the regeneration of the damaged epithelium and the regulation of inflammation could be considered as therapeutic options for individuals with IBD. Several members of the transforming growth factor (TGF)-β superfamily, particularly TGF-β, activin and follistatin, are key candidates as they exhibit various roles in inflammatory processes and contribute to maintenance and homeostasis in the GI tract. This article aimed firstly to review the events involved in the pathogenesis of IBD with particular emphasis on TGF-β, activin and follistatin and secondly to outline the potential role of therapeutic manipulation of these pathways. [ABSTRACT FROM AUTHOR]

Women of African ancestry have lower incidence of epithelial ovarian cancer (EOC) yet worse survival compared to women of European ancestry. We conducted a genome-wide association study in African ancestry women with 755 EOC cases, including 537 high-grade serous ovarian carcinomas (HGSOC) and 1,235 controls. We identified four novel loci with suggestive evidence of association with EOC (p

Junlu Tong1,2 &ast;, Li Cong1 &ast;, Yingbin Jia,3 Bai-Liang He,4 Yifan Guo,1 Jianzhong He,5 Decheng Li,3 Baojia Zou,3 Jian Li3 1Department of Endocrinology, The Fifth Affiliated Hospital of Sun Yat-sen University, Zhuhai, People’s Republic of China; 2Department of Central Laboratory, The Fifth Affiliated Hospital of Sun Yat-sen University, Zhuhai, People’s Republic of China; 3Department of Hepatobiliary Surgery, The Fifth Affiliated Hospital of Sun Yat-sen University, Zhuhai, People’s Republic of China; 4Guangdong Provincial Key Laboratory of Biomedical Imaging, Guangdong Provincial Engineering Research Center of Molecular Imaging, The Fifth Affiliated Hospital of Sun Yat-sen University, Zhuhai, People’s Republic of China; 5Department of Pathology, The Fifth Affiliated Hospital of Sun Yat-sen University, Zhuhai, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Jian Li; Baojia Zou, Department of Hepatobiliary Surgery, The Fifth Affiliated Hospital of Sun Yat-sen University, Zhuhai, People’s Republic of China, Tel +86-756-252-8781, Email lijian5@mail.sysu.edu.cn; zoubj6@mail.sysu.edu.cnPurpose: In this study, we aimed to investigate the effect of follistatin (FST) on hepatic steatosis in NAFLD and the underlying mechanism, which has rarely been reported before.Methods: Liver samples from NAFLD patients and normal liver samples (from liver donors) were collected to investigate hepatic FST expression in humans. Additionally, human liver cells (LO2) were treated with free fatty acid (FFA) to induce lipid accumulation. Furthermore, lentivirus with FST overexpression or knockdown vectors were used to generate stable cell lines, which were subsequently treated with FFA or FFA and rapamycin. In the animal experiments, male C57BL/6J mice were fed with a high-fat diet (HFD) to induce NAFLD, after which the adeno-associated virus (AAV) gene vectors for FST overexpression were administered. In both cell culture and mice, we evaluated morphological changes and the protein expression of sterol regulatory element-binding protein1 (SREBP1), acetyl-CoA carboxylase1 (ACC1), carbohydrate-responsive element-binding protein (ChREBP), fatty acid synthase (FASN), and Akt/mTOR signaling. The body weight and serum parameters of the mice were also measured.Results: Hepatic FST expression level was higher in NAFLD patients compared to normal samples. In LO2 cells, FST overexpression alleviated lipid accumulation and lipogenesis, whereas FST knockdown aggravated hepatic steatosis. FST could regulate Akt/mTOR signaling, and the mTOR inhibitor rapamycin abolished the effect of FST knockdown on hepatic de novo lipogenesis (DNL). Furthermore, FST expression was increased in HFD mice compared to the corresponding controls. FST overexpression in mice reduced body weight gain, hyperlipidemia, hepatic DNL, and suppressed Akt/mTOR signaling.Conclusion: Hepatic FST expression increases in NAFLD and plays a protective role in hepatic steatosis. FST overexpression gene therapy alleviates hepatic steatosis via the mTOR pathway.Therefore, gene therapy for FST is a promising treatment in NAFLD.Keywords: follistatin, non-alcoholic fatty liver disease, free fatty acid, lipid synthesis

The clinical success of neutralizing vascular endothelial growth factor (VEGF) has unequivocally identified VEGF as a driver of retinal edema that underlies a variety of blinding conditions. VEGF is not the only input that is received and integrated by the endothelium. For instance, the permeability of blood vessels is also regulated by the large and ubiquitously expressed transforming growth factor beta (TGF-β) family. In this project, we tested the hypothesis that members of the TGF-β family influence the VEGF-mediated control of the endothelial cell barrier. To this end, we compared the effect of bone morphogenetic protein-9 (BMP-9), TGF-β1, and activin A on the VEGF-driven permeability of primary human retinal endothelial cells. While BMP-9 and TGF-β1 had no effect on VEGF-induced permeability, activin A limited the extent to which VEGF relaxed the barrier. This activin A effect was associated with the reduced activation of VEGFR2 and its downstream effectors and an increased expression of vascular endothelial tyrosine phosphatase (VE-PTP). Attenuating the expression or activity of VE-PTP overcame the effect of activin A. Taken together, these observations indicate that the TGF-β superfamily governed VEGF-mediated responsiveness in a ligand-specific manner. Furthermore, activin A suppressed the responsiveness of cells to VEGF, and the underlying mechanism involved the VE-PTP-mediated dephosphorylation of VEGFR2. [ABSTRACT FROM AUTHOR]

The activin–follistatin system regulates several cellular processes, including differentiation and tumorigenesis. We hypothesized that the immunostaining of βA-activin and follistatin varies in neoplastic cervical lesions. Cervical paraffin-embedded tissues from 162 patients sorted in control (n = 15), cervical intraepithelial neoplasia (CIN) grade 1 (n = 38), CIN2 (n = 37), CIN3 (n = 39), and squamous cell carcinoma (SCC; n = 33) groups were examined for βA-activin and follistatin immunostaining. Human papillomavirus (HPV) detection and genotyping were performed by PCR and immunohistochemistry. Sixteen samples were inconclusive for HPV detection. In total, 93% of the specimens exhibited HPV positivity, which increased with patient age. The most detected high-risk (HR)-HPV type was HPV16 (41.2%) followed by HPV18 (16%). The immunostaining of cytoplasmatic βA-activin and follistatin was higher than nuclear immunostaining in all cervical epithelium layers of the CIN1, CIN2, CIN3, and SCC groups. A significant decrease (p < 0.05) in the cytoplasmic and nuclear immunostaining of βA-activin was detected in all cervical epithelial layers from the control to the CIN1, CIN2, CIN3, and SCC groups. Only nuclear follistatin immunostaining exhibited a significant reduction (p < 0.05) in specific epithelial layers of cervical tissues from CIN1, CIN2, CIN3, and SCC compared to the control. Decreased immunostaining of cervical βA-activin and follistatin at specific stages of CIN progression suggests that the activin–follistatin system participates in the loss of the differentiation control of pre-neoplastic and neoplastic cervical specimens predominantly positive for HPV. [ABSTRACT FROM AUTHOR]

Reproductive traits are affected by many factors, including ovarian function, hormones, and genetics. Genetic polymorphisms of candidate genes are associated with reproductive traits. Several candidate genes are associated with economic traits, including the follistatin (FST) gene. Thus, this study aimed to evaluate whether the genetic variations in the FST gene are associated with the reproductive traits in Awassi ewes. The genomic DNA was extracted from 109 twin ewes and 123 single-progeny ewes. Therefore, 4 sequence fragments from the FST gene were amplified using polymerase chain reaction (PCR) (exon 2/240, exon 3/268, exon 4/254, and exon 5/266 bp, respectively). For a 254 bp amplicon, 3 genotypes were identified: CC, CG, and GG. Sequencing revealed a novel mutation in CG genotypes c.100C > G. The statistical analysis of c.100C > G showed an association with reproductive characteristics. Ewes carrying the c.100C > G had significantly (P ⩽.01) lower litter sizes, twinning rates, lambing rates, and more days to lambing compared with CG and CC genotypes. Logistic regression analysis confirmed that the c.100C > G single-nucleotide polymorphism (SNP) is responsible for decreasing litter size. According to these results, the variant c.100C > G negatively affects the traits of interest and is associated with lower reproductive traits in Awassi sheep. As a result of this study, ewes carrying the c.100C > G SNP have lower litter size and are less prolific. [ABSTRACT FROM AUTHOR]

OBJECTIVE: Follistatin-like protein 1 (FSTL-1) and follistatin-like protein 3 (FSTL-3) are glycoproteins whose associations with inflammatory cytokines were reported in previous studies. However, it is not yet known whether they have an effect on the pathogenesis of familial Mediterranean fever (FMF). We aimed to detect the FSTL-1 and FSTL-3 levels and to determine their relationship to the attack status and mutation types in patients with FMF. METHODS: Fifty-six FMF patients and 22 healthy controls (HCs) were included in the study. Serum FSTL-1 and FSTL-3 levels were measured with the enzyme-linked immunosorbent assay method from collected serum samples. In addition, the MEditerranean FeVer (MEFV) gene mutation types of the patients were noted. RESULTS: Serum FSTL-1 levels were significantly higher in FMF patients than in HCs (p=0.005). However, there was no significant difference in FSTL-1 levels between patients in the attack period (n=26) and in the attack-free period (n=30). FSTL-3 levels were similar between FMF patients and HCs or patients in the attack period and in the attack-free period. Furthermore, the MEFV mutation type and attack status had no significant effect on FSTL-1 and FSTL-3 levels (p>0.05). CONCLUSION: Our results suggest that FSTL-1 may be associated with the pathogenesis of FMF, rather than FSTL-3. However, neither serum FSTL-1 nor FSTL-3 seems to be good markers to reflect inflammatory activity. [ABSTRACT FROM AUTHOR]

The interactions between muscle and bone are noted in the clinical relationships between sarcopenia and osteoporosis. Myokines secreted from the skeletal muscles play roles in muscle-bone interactions related to various physiological and pathophysiological states. Although numerous evidence suggests that growth hormone (GH) influences both muscle and bone, the effects of GH on the muscle-bone interactions have remained unknown. We, therefore, investigated the influences of GH administration for 8 weeks on muscle and bone, including myokine expression, in mice with or without ovariectomy (OVX). GH administration significantly increased muscle mass in the whole body and lower limbs, as well as tissue weights of the extensor digitorum longus (EDL) and soleus muscles in mice with or without OVX. Moreover, it markedly increased grip strength in both mice. As for femurs, GH administration significantly increased cortical thickness and area in mice with or without OVX. Moreover, GH significantly blunted the decrease in the ratio of bone volume to tissue volume at the trabecular bone in mice with OVX. GH administration significantly decreased follistatin mRNA levels in the EDL, but not the soleus, muscles in mice with or without OVX, although it did not affect the other myokines examined. However, GH administration significantly elevated serum follistatin levels in mice. In conclusion, this study indicates that GH administration increases skeletal muscle mass and grip strength and cortical and trabecular bone-related parameters obtained by micro-computed tomography analyses in mice. However, myokine regulation might not be critical for the effects of GH on muscle and bone. [ABSTRACT FROM AUTHOR]

This study investigated the effect of concurrent training (CT) sequences on fibroblast growth factor 21 (FGF21), irisin, myostatin (MSTN), and follistatin (FST) among adults with type 2 diabetes mellitus (T2DM). Fifty-one diabetic men were randomly selected and assigned to concurrent aerobic-resistance (A-R) training and concurrent resistance-aerobic (R-A) training, and non-exercise control (CON) groups. The training protocols consisted of three sessions per week for 12 weeks. The A-R and R-A groups received the same CT protocols and performed with different sequences. The subjects' blood samples were obtained at baseline and 48 hours after the last session of the intervention. The results showed that the concentration of FGF21 did not change significantly after the 12 weeks of CT with different sequences (p >.05, η2 = 0.123), but the serum concentration of irisin (A-R = 2.93 μg.L–1 (95% CI = 1.45–4.42, d = −0.57) and R-A = 3.31 μg.L–1 (95% CI = 1.13–5.49, d = −0.68)) and FST (A-R = 4.96 ng.mL–1 (95% CI = 3.41–6.5, d = −0.39) and R-A = 4.19 ng.mL–1 (95% CI = 2.82–5.56, d = –0.55)) significantly increased while the serum MSTN concentration (A-R = 152.32 ng.L–1 (95% CI = 61.83–242.82, d = 1.31) and R-A = 173 ng.L–1 (95% CI = 35.89–227.5, d = 0.83)) of both A-R and R-A groups mainly decreased (p <.01). There was no significant difference between A-R and R-A groups' irisin, FST, and MSTN concentration (p >.05), though the CT improved the body compositions, strength, and peak oxygen uptake in both groups (p <.01). Regardless of the CT sequences, it was found that CT acted as a therapeutic modality of training for T2DM patients by increasing their irisin and FST and decreasing their MSTN concentrations. [ABSTRACT FROM AUTHOR]