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Embryo implantation remains a significant challenge for assisted reproductive technology, with implantation failure occurring in ∼50% of in vitro fertilization attempts. Understanding the molecular mechanisms underlying uterine receptivity will enable the development of new interventions and biomarkers. TGFβ family signaling in the uterus is critical for establishing and maintaining pregnancy. Follistatin (FST) regulates TGFβ family signaling by selectively binding TGFβ family ligands and sequestering them. In humans, FST is up-regulated in the decidua during early pregnancy, and women with recurrent miscarriage have lower endometrial expression of FST during the luteal phase. Because global knockout of Fst is perinatal lethal in mice, we generated a conditional knockout (cKO) of Fst in the uterus using progesterone receptor-cre to study the roles of uterine Fst during pregnancy. Uterine Fst-cKO mice demonstrate severe fertility defects and deliver only 2% of the number of pups delivered by control females. In Fst-cKO mice, the uterine luminal epithelium does not respond properly to estrogen and progesterone signals and remains unreceptive to embryo attachment by continuing to proliferate and failing to differentiate. The uterine stroma of Fst-cKO mice also responds poorly to artificial decidualization, with lower levels of proliferation and differentiation. In the absence of uterine FST, activin B expression and signaling are up-regulated, and bone morphogenetic protein (BMP) signals are impaired. Our findings support a model in which repression of activin signaling by FST enables uterine receptivity by preserving critical BMP signaling.

Follistatin‐like (FSTL) family members are associated with cancer progression. However, differences between FSTL members with identical cancer types have not been systematically investigated. Among the most malignant tumours worldwide, colorectal cancer (CRC) has high metastatic potential and chemoresistance, which makes it challenging to treat. A systematic examination of the relationship between the expression of FSTL family members in CRC will provide valuable information for prognosis and therapeutic development. Based on large cohort survival analyses, we determined that FSTL3 was associated with a significantly worse prognosis in CRC at the RNA and protein levels. Immunohistochemistry staining of CRC specimens revealed that FSTL3 expression levels in the cytosol were significantly associated with a poor prognosis in terms of overall and disease‐free survival. Molecular simulation analysis showed that FSTL3 participated in multiple cell motility signalling pathways via the TGF‐β1/TWIST1 axis to control CRC metastasis. The findings provide evidence of the significance of FSTL3 in the oncogenesis and metastasis of CRC. FSTL3 may be useful as a diagnostic or prognostic biomarker, and as a potential therapeutic target.

The placenta is the interface between mother and fetus and inadequate function contributes to short and long-term ill-health. The placenta is absent from most large-scale RNA-Seq datasets. We therefore analyze long and small RNAs (~101 and 20 million reads per sample respectively) from 302 human placentas, including 94 cases of preeclampsia (PE) and 56 cases of fetal growth restriction (FGR). The placental transcriptome has the seventh lowest complexity of 50 human tissues: 271 genes account for 50% of all reads. We identify multiple circular RNAs and validate 6 of these by Sanger sequencing across the back-splice junction. Using large-scale mass spectrometry datasets, we find strong evidence of peptides produced by translation of two circular RNAs. We also identify novel piRNAs which are clustered on Chr1 and Chr14. PE and FGR are associated with multiple and overlapping differences in mRNA, lincRNA and circRNA but fewer consistent differences in small RNAs. Of the three protein coding genes differentially expressed in both PE and FGR, one encodes a secreted protein FSTL3 (follistatin-like 3). Elevated serum levels of FSTL3 in pregnant women are predictive of subsequent PE and FGR. To aid visualization of our placenta transcriptome data, we develop a web application ( https://www.obgyn.cam.ac.uk/placentome/ ). Placental dysfunction can have catastrophic or barely discernible effects ranging from miscarriage to apparently normal birth. Here the authors present a comprehensive analysis of the human placental transcriptome and identify circular RNAs and piRNAs.

The significance of cardiac stem cell (CSC) populations for cardiac regeneration remains disputed. Here, we apply the most direct definition of stem cell function (the ability to replace lost tissue through cell division) to interrogate the existence of CSCs. By single-cell mRNA sequencing and genetic lineage tracing using two Ki67 knockin mouse models, we map all proliferating cells and their progeny in homoeostatic and regenerating murine hearts. Cycling cardiomyocytes were only robustly observed in the early postnatal growth phase, while cycling cells in homoeostatic and damaged adultmyocardium represented various noncardiomyocyte cell types. Proliferative postdamage fibroblasts expressing follistatin-like protein 1 (FSTL1) closely resemble neonatal cardiac fibroblasts and form the fibrotic scar. Genetic deletion of Fstl1 in cardiac fibroblasts results in postdamage cardiac rupture. We find no evidence for the existence of a quiescent CSC population, for transdifferentiation of other cell types toward cardiomyocytes, or for proliferation of significant numbers of cardiomyocytes in response to cardiac injury.

Background/Objectives: To investigate associations between Follistatin (FST) gene polymorphisms (SNPs) and baseline musculoskeletal traits, and their interactions with 16-week exercise interventions. Methods: A cohort of 470 untrained Northern Han Chinese adults (208 males, 262 females), sourced from the “Research on Key Technologies for an Exercise and Fitness Expert Guidance System” project, was analyzed. These participants were previously randomly assigned to one of four exercise groups (Hill, Running, Cycling, Combined) or a non-exercising Control group, and completed their respective 16-week protocols. Body composition, bone mineral content (BMC), bone mineral density (BMD), and serum follistatin levels were all assessed pre- and post-intervention. Dual-energy X-ray absorptiometry (DXA) was utilized for the body composition, BMC, and BMD measurements. FST SNPs (rs3797296, rs3797297) were genotyped using matrix assisted laser desorption/ionization time-of-flight mass spectrometer (MALDI-TOF MS) or microarrays. To elucidate the biological mechanisms, we performed in silico functional analyses for rs3797296 and rs3797297. Results: Baseline: In females only, the rs3797297 T allele was associated with higher muscle mass (β = 1.159, 95% confidence interval (CI): 0.202–2.116, P_adj = 0.034) and BMC (β = 0.127, 95% CI: 0.039–0.215, P_adj = 0.009), with the BMC effect significantly mediated by muscle mass. Exercise Response: Interventions improved body composition, particularly in females. Gene-Exercise Interaction: A significant interaction occurred exclusively in women undertaking hill climbing: the rs3797296 G allele was associated with attenuated muscle mass gains (β = −1.126 kg, 95% CI: −1.767 to −0.485, P_adj = 0.034). Baseline follistatin correlated with body composition (stronger in males) and increased post-exercise (primarily in males, Hill/Running groups) but did not mediate SNP effects on exercise adaptation. Functional annotation revealed that rs3797297 is a likely causal variant, acting as a skeletal muscle eQTL for the mitochondrial gene NDUFS4, suggesting a mechanism involving muscle bioenergetics. Conclusions: Findings indicate that FST polymorphisms associate with musculoskeletal traits in Northern Han Chinese. Mechanistic insights from functional annotation reveal potential pathways for these associations, highlighting the potential utility of these genetic markers for optimizing training program design.

Abstract Background and Aims Follistatin-like protein-1 (FSTL-1) is considered to be an adipokine or myokine that could be a potential regulator of metabolism. Our purpose is to investigate the relationship between circulating FSTL-1 levels and insulin resistance (IR) in type 2 diabetes mellitus (T2DM) and to identify the regulatory factors. Methods FSTL-1 expression in C57BL/6J and db/db mice was examined by quantitative reverse transcriptase–polymerase chain reaction (qRT-PCR) and Western blots. Serum FSTL-1 levels were measured by enzyme-linked immunosorbent assay in 298 T2DM patients and 202 healthy controls. Changes in the circulating FSTL-1 level were observed during the oral glucose tolerance test, EHC (euglycemic-hyperinsulinemic clamp), lipid infusion, acute exercise, and cold-exposure test. Results We found that FSTL-1 protein expression in the adipose tissue of db/db mice was significantly higher than that of wild-type mice. Importantly, circulating FSTL-1 levels in T2DM and overweight/obese participants were higher than those in healthy and lean individuals, and was related to HOMA-IR, adiponectin, and obesity- and metabolism-related parameters. In the intervention study, 45 minutes of physical activity was found to significantly increase the circulating FSTL-1 concentration in young, healthy participants. Further, FSTL-1 protein expression in adipose tissue rose dramatically in response to physical activity in mice. Hyperinsulinemia during EHC and acute elevated FFA induced by lipid infusion resulted in a significant decrease in the circulating FSTL-1 levels. However, no change was found in the circulating FSTL-1 levels in response to the oral glucose challenge or cold-exposure test. Conclusions FSTL-1 may be an adipomyokine associated with insulin resistance and physical activity, and circulating FSTL-1 levels are increased in patients with T2DM.

PurposeDue to the mechanistic role of myostatin and follistatin in modulating muscle mass, shifts in the follistatin to myostatin ratio (F:M) may help explain changes in muscular size in response to resistance training (RT). The present study examined whether differential responses in follistatin and myostatin occur based on the amount of active musculature in a RT program in middle-aged men.MethodsForty middle-aged men (age = 46.5 ± 3.1 years) were randomly assigned to 1 of 4 groups, upper-body RT (UB; n = 10), lower-body RT (LB; n = 10), combined RT (UB + LB; n = 10) or control (C; n = 10). The training protocol consisted of three exercise sessions per week for 8 weeks. Blood samples were obtained at baseline and 48 h after the final session of the training program.ResultsMuscle mass significantly increased (p < 0.05) following UB = 0.76 ± 0.46 kg, LB = 0.90 ± 0.29 kg, UB + LB = 1.38 ± 0.70 kg, compared to no changes after control. Serum follistatin increased in the LB = 0.24 ± 0.06 ng mL−1, UB = 0.27 ± 0.17 ng mL−1, UB + LB = 0.50 ± 0.18 ng mL−1, while serum myostatin decreased in the LB = − 0.11 ± 0.08 ng mL−1 and UB + LB = − 0.34 ± 0.23 ng mL−1, but not UB = 0.07 ± 0.16 ng mL−1. Further, change in concentration following training was larger between UB + LB and either LB or UB alone for both follistatin and myostatin.ConclusionsBoth UB and LB increase muscle mass and alter the F: M ratio; however, the change in these endocrine markers is approximately twice as large if UB and LB is combined. The endocrine response to RT of myostatin and follistatin may depend on the volume of muscle mass activated during training.

Follistatin-like protein 1 (FSTL1), a secreted glycoprotein, serves a key role in regulating various biological processes. The present review explores the molecular mechanisms through which FSTL1 influences inflammation, cellular senescence and tumour progression. As a multifunctional protein with both autocrine and paracrine properties, FSTL1 regulates cell survival, proliferation, differentiation and migration, while also modulating immune responses. Evidence indicates that FSTL1 exerts context-dependent regulatory effects on pathological conditions by modulating signalling pathways, such as TGF-β, NF-κB and MAPK. Furthermore, increased FSTL1 expression has been found in the inflammatory synovial tissues of patients with osteoarthritis and it contributes to nucleus pulposus cell inflammation. In conclusion, the distinctive structural features and widespread expression of FSTL1 position it as a key target for understanding the mechanisms underlying inflammation, senescence and tumourigenesis, providing potential options for novel diagnostic and therapeutic strategies for these conditions.

Background In adipose tissue–muscle crosstalk mechanisms, the interaction of adipokines and myokines is known to be critical for maintaining the body's metabolic balance in age‐related metabolic disorders. The aim of the study investigate the effects of 12 weeks of aerobic and resistance exercise training on spexin and follistatin and their relationship with each other. Methods This study was a multicentre, randomized controlled study conducted at two assisted living facilities with participants aged ≥ 65. Among the 66 subjects, 33 were allocated to the exercise group (E) and 33 to the control group (C). The exercise group was administered 50 min of exercise by expert physiotherapists 1 day a week for 12 weeks. Participants in the intervention groups performed exercise assignments two extra days a week, tailored to their specific circumstances and supervised by the institution's physiotherapists. Spexin, follistatin and measurements of metabolic syndrome parameters were performed at the beginning and after 12 weeks. Results The mean age of the 62 participants who completed the study (E n = 31, C n = 31) was 73.25 ± 6.44 years, and 62.9% were female. While spexin (E = 1090.94 ± 533.66, C = 1142.91 ± 550.68 pg/mL, p > 0.05) and follistatin (E = 50.52 ± 24.35, C = 50.00 ± 23.52 ng/mL, p > 0.05) values were similar in the two groups at baseline, the values of spexin (E = 1311.32 ± 513.66, C = 1033.27 ± 486.48, p < 0.0001; η2 = 0.387) and follistatin (E = 64.79 ± 32.35, C = 48.16 ± 26.27, p < 0.0001; η2 = 0.267) in the exercise group were higher than in the control group at week 12. At the 12th week, neck circumference (38.32 ± 3.41, 37.16 ± 3.15, p = 0.002), waist circumference (102.64 ± 13.38, 98.54 ± 14.47, p < 0.0001), hip circumference (105.70 ± 15.43, 102.93 ± 13.48, p < 0.0001), body fat mass (22.69 ± 7.39, 20.45 ± 6.22, p < 0.0001) and systolic and diastolic blood pressure (137.19 ± 13.80, 124.9 ± 15.18, p = 0.0001, 77.38 ± 12.10, 72.61 ± 9.26, p = 0.043) decreased, and body muscle mass (46.32 ± 8.43, 49.03 ± 8.58, p < 0.0001) increased in the exercise group compared to baseline. A correlation was observed between the change in follistatin level and the change in spexin level (r = 0.438, p = 0.001). A negative correlation was found between the amount of decrease in body fat mass and the decrease in spexin level (r = −0.380, p = 0.005). A positive correlation was found between the increase in body muscle mass and the increase in spexin and follistatin (r = 0.431, p = 0.001; r = 0.490, p < 0.0001, respectively). Conclusions It was found that spexin, which provides metabolic homeostasis, and follistatin, which expresses the increase in muscle mass, increased with the implementation of a 12‐week aerobic and resistance exercise program in elderly individuals, and these increases were found to be associated with each other. Trial Registration ClinicalTrials.gov identifier: NCT05251597

MASLD (metabolic-associated steatotic liver disease) and MASH (steatohepatitis) are closely associated with hepatic IR (insulin resistance) and T2D. Regardless, insulin-stimulated hepatic lipogenesis is considered essential for MASLD development, as mouse models of complete hepatic IR become diabetic without MASLD when fed high-fat diets. Challenging this notion, we found that male LDKO mice lacking hepatic insulin receptor substrates acutely developed MASLD if fed a fructose-enriched “MASH diet” (GAN) or high-fructose diet. Fructose potentiated hepatic re-esterification of abundant circulating fatty acids in LDKO mice, evidenced by excess 13 C incorporation into the glycerol backbone—but not fatty acid chains—of hepatic triacylglyceride after gavage with [U 13 C]fructose. Suppressing adipose lipolysis in LDKO mice by inactivating hepatic Fst (Follistatin) prevented acute MASLD, whereas over-expressing Fst in wild-type mouse liver accelerated GAN-promoted MASLD/MASH. Compatibly, higher serum FST levels among Tübingen Diabetes Family Study participants clustered with increased adipose IR and greater hepatic triacylglyceride accumulation. The authors report that, in mice without hepatic insulin signaling, diets high in fructose cause acute hepatic steatosis without increasing hepatic de novo lipogenesis, dependent upon hepatic follistatin secretion and associated adipose insulin resistance.