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KLB dysregulation mediates disrupted muscle development in intrauterine growth restriction.

ABSTRACT: Intrauterine growth restriction (IUGR) is a leading cause of neonatal morbidity and mortality in humans and domestic animals. Developmental adaptations of skeletal muscle in IUGR lead to increased risk of premature muscle loss and metabolic disease in later life. Here, we identified β-Klotho (KLB), a fibroblast growth factor 21 (FGF21) co-receptor, as a novel regulator of muscle development in IUGR. Using the pig as a naturally-occurring disease model, we performed transcriptome-wide profiling of fetal muscle (day 90 of pregnancy) from IUGR and normal-weight (NW) littermates. We found that, alongside large-scale transcriptional changes comprising multiple developmental, tissue injury and metabolic gene pathways, KLB was increased in IUGR muscle. Moreover, FGF21 concentrations were increased in plasma in IUGR fetuses. Using cultures of fetal muscle progenitor cells (MPCs), we showed reduced myogenic capacity of IUGR compared to NW muscle in vitro, as evidenced by differences in fusion indices and myogenic transcript levels, as well as mechanistic target of rapamycin (mTOR) activity. Moreover, transfection of MPCs with KLB small interfering RNA promoted myogenesis and mTOR activation, whereas treatment with FGF21 had opposite and dose-dependent effects in porcine and also in human fetal MPCs. In conclusion, our results identify KLB as a novel and potentially critical mediator of impaired muscle development in IUGR, through conserved mechanisms in pigs and humans. Our data shed new light onto the pathogenesis of IUGR, a significant cause of lifelong ill-health in humans and animals. KEY POINTS: Intrauterine growth restriction (IUGR) is associated with large-scale transcriptional changes in developmental, tissue injury and metabolic gene pathways in fetal skeletal muscle. Levels of the fibroblast growth factor 21 (FGF21) co-receptor, β-Klotho (KLB) are increased in IUGR fetal muscle, and FGF21 concentrations are increased in IUGR fetal plasma. KLB mediates a reduction in muscle development through inhibition of mechanistic target of rapamycin signalling. These effects of KLB on muscle cells are conserved in pig and human, suggesting a vital role of this protein in the regulation of muscle development and function in mammals.

SUBMITTER: Cortes-Araya Y

PROVIDER: S-EPMC9303651 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:This study was performed to identify transcriptional alterations in male intrauterine growth restricted (IUGR) rats during and at the end of nephrogenesis in order to generate hypotheses which molecular mechanisms contribute to adverse kidney programming. IUGR was induced by low protein (LP) diet throughout pregnancy, bilateral uterine vessel ligation (LIG), or intrauterine stress (IUS) by sham operation. Offspring of unimpaired dams served as controls. Significant acute kidney damage was ruled out by negative results for proteins indicative of ER-stress, autophagy, apoptosis, or infiltration with macrophages. Renal gene expression was examined by transcriptome microarrays, demonstrating 53 (LP, n = 12; LIG, n = 32; IUS, n = 9) and 134 (LP, n = 10; LIG, n = 41; IUS, n = 83) differentially expressed transcripts on postnatal days (PND) 1 and 7, respectively. Reduced Pilra (all IUGR groups, PND 7), Nupr1 (LP and LIG, PND 7), and Kap (LIG, PND 1) as well as increased Ccl20, S100a8/a9 (LIG, PND 1), Ifna4, and Ltb4r2 (IUS, PND 7) indicated that inflammation-related molecular dysregulation could be a "common" feature after IUGR of different origins. Network analyses of transcripts and predicted upstream regulators hinted at proinflammatory adaptions mainly in LIG (arachidonic acid-binding, neutrophil aggregation, toll-like-receptor, NF-kappa B, and TNF signaling) and dysregulation of AMPK and PPAR signaling in LP pups. The latter may increase susceptibility towards obesity-associated kidney damage. Western blots of the most prominent predicted upstream regulators confirmed significant dysregulation of RICTOR in LP (PND 7) and LIG pups (PND 1), suggesting that mTOR-related processes could further modulate kidney programming in these groups of IUGR pups. KEY MESSAGES: Inflammation-related transcripts are dysregulated in neonatal IUGR rat kidneys. Upstream analyses indicate renal metabolic dysregulation after low protein diet. RICTOR is dysregulated after low protein diet and uterine vessel ligation.

Project description:BACKGROUND:Preeclampsia and intrauterine growth restriction are placental dysfunction-related disorders (PDDs) that require a referral decision be made within a certain time period. An appropriate prediction model should be developed for these diseases. However, previous models did not demonstrate robust performances and/or they were developed from datasets with highly imbalanced classes. OBJECTIVE:In this study, we developed a predictive model of PDDs by machine learning that uses features at 24-37 weeks' gestation, including maternal characteristics, uterine artery (UtA) Doppler measures, soluble fms-like tyrosine kinase receptor-1 (sFlt-1), and placental growth factor (PlGF). METHODS:A public dataset was taken from a prospective cohort study that included pregnant women with PDDs (66/95, 69%) and a control group (29/95, 31%). Preliminary selection of features was based on a statistical analysis using SAS 9.4 (SAS Institute). We used Weka (Waikato Environment for Knowledge Analysis) 3.8.3 (The University of Waikato, Hamilton, NZ) to automatically select the best model using its optimization algorithm. We also manually selected the best of 23 white-box models. Models, including those from recent studies, were also compared by interval estimation of evaluation metrics. We used the Matthew correlation coefficient (MCC) as the main metric. It is not overoptimistic to evaluate the performance of a prediction model developed from a dataset with a class imbalance. Repeated 10-fold cross-validation was applied. RESULTS:The classification via regression model was chosen as the best model. Our model had a robust MCC (.93, 95% CI .87-1.00, vs .64, 95% CI .57-.71) and specificity (100%, 95% CI 100-100, vs 90%, 95% CI 90-90) compared to each metric of the best models from recent studies. The sensitivity of this model was not inferior (95%, 95% CI 91-100, vs 100%, 95% CI 92-100). The area under the receiver operating characteristic curve was also competitive (0.970, 95% CI 0.966-0.974, vs 0.987, 95% CI 0.980-0.994). Features in the best model were maternal weight, BMI, pulsatility index of the UtA, sFlt-1, and PlGF. The most important feature was the sFlt-1/PlGF ratio. This model used an M5P algorithm consisting of a decision tree and four linear models with different thresholds. Our study was also better than the best ones among recent studies in terms of the class balance and the size of the case class (66/95, 69%, vs 27/239, 11.3%). CONCLUSIONS:Our model had a robust predictive performance. It was also developed to deal with the problem of a class imbalance. In the context of clinical management, this model may improve maternal mortality and neonatal morbidity and reduce health care costs.

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KLB dysregulation mediates disrupted muscle development in intrauterine growth restriction.

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