Postnatal Growth Research Articles

Early postnatal growth failure in infants

Postnatal growth failure (PGF), a multifactorial condition is common in preterm infants and infants born weighing <1500g and is associated with impaired neurodevelopmental and growth outcomes. In low-resource settings, like Uganda, parenteral nutrition and breastmilk fortifier are often unavailable, and preterm infants rely solely on their mother's expressed breastmilk, which can be inadequate. This retrospective cohort study, conducted in a level II neonatal unit in eastern Uganda, aimed to evaluate the incidence of and risk factors for postnatal growth failure among infants <1500g. The study included infants with birthweight <1500g, admitted within 24h of birth, and who spent 7 or more days in the neonatal unit. Major congenital malformations or a diagnosis of hypoxic ischemic encephalopathy were exclusion criteria. PGF was defined as a decrease in weight Z score between birth and discharge of more than - 1.28. Data on feeding, anthropometry, co-morbidities, and clinical measures were extracted from medical records. Statistical analyses were performed using Stata 17.0 with crude and adjusted relative risks (RR) were reported. One hundred and four infants were recruited, including 47 (45.2%) male and 57 (54.8%) female, with a mean birth weight of 1182g (SD 18g, 95% CI: 1140, 1210). Almost half were small for gestational age, most were singletons (66.3%), and most were born by spontaneous vaginal delivery (82.7%). PGF was observed at discharge in 75.9% (N = 79). Clinical risk factors for PGF included: small for gestational age (cRR 1.25, 95% CI: 1.01, 1.53), respiratory distress syndrome (aRR 1.30 95% CI: 1.01, 1.67), duration of bubble continuous positive airway pressure use (aRR 1.35, 95% CI: 1.10, 1.66), sepsis requiring second line (aRR 1.58, 95% CI: 1.22, 2.04) and third line treatment (aRR 1.46, 95% CI: 1.20, 1.77), prolonged time to achieve full feeds (aRR 1.30, 95% CI: 1.01, 1.66) and prolonged hospitalisation (aRR 1.85, 95% CI: 1.31, 2.61). PGF was common among infants <1500g in this hospitalised cohort who were primarily fed on their mother's own milk. Urgent action is needed to enhance postnatal growth in this vulnerable patient group. Future research should focus on exploring multidisciplinary interventions that can improve growth outcomes in this population and understanding the long-term implications and need for care for these infants.

Homozygous synonymous FAM111A variant underlies an autosomal recessive form of Kenny-Caffey syndrome.

FAM111A (family with sequence similarity 111 member A) is a serine protease and removes covalent DNA-protein cross-links during DNA replication. Heterozygous gain-of-function variants in FAM111A cause skeletal dysplasias, such as the perinatal lethal osteocraniostenosis and the milder Kenny-Caffey syndrome (KCS). We report two siblings born to consanguineous parents with dysmorphic craniofacial features, postnatal growth retardation, ophthalmologic manifestations, hair and nail anomalies, and skeletal abnormalities such as thickened cortex and stenosis of the medullary cavity of the long bones suggestive of KCS. Using exome sequencing, a homozygous synonymous FAM111A variant, NM_001312909.2:c.81 G > A; p.Pro27=, that affects the last base of the exon and is predicted to alter FAM111A pre-mRNA splicing, was identified in both siblings. We identified aberrantly spliced FAM111A transcripts, reduced FAM111A mRNA levels, and near-complete absence of FAM111A protein in fibroblasts of both patients. After treatment of patient and control fibroblasts with different concentrations of camptothecin that induces covalent DNA-protein cross-links, we observed a tendency towards a reduced proportion of metabolically active cells in patient compared to control fibroblasts. However, under these culture conditions, we did not find consistent and statistically significant differences in cell cycle progression and apoptotic cell death between patient and control cells. Our findings show that FAM111A deficiency underlies an autosomal recessive form of FAM111A-related KCS. Based on our results and published data, we hypothesize that loss of FAM111A and FAM111A protease hyperactivity, as observed for gain-of-function patient-variant proteins, may converge on a similar pathomechanism underlying skeletal dysplasias.

Thermal equilibrium as a predictor of growth efficiency in preterm infants

IntroductionProviding adequate nutrition to preterm infants to achieve postnatal growth similar to intrauterine growth remains challenging due to the unpredictability of individual determinants.Material and methodsWe used a calculation program for infant incubators to compare the estimated heat balance with the caloric intake and growth rate in Very Low Birth Weight Infants (VLBWI).Results and discussionA group of 32 VLBWI was studied over a period of 14–28 days. An interrelationship between thermal equilibrium and growth rate was observed, with standardized incubator settings being unable to avoid periods of negative thermal balance and concomitantly poor growth rate.ConclusionDetermining personalized incubator settings by means of a calculation program could help improve nutrition and growth in preterm infants.

Female sex hormones inversely regulate acute kidney disease susceptibility throughout life.

While epidemiological and experimental studies have demonstrated kidney-protective effects of estrogen and female sex in adulthood, some epidemiological data showed deterioration of kidney function during puberty when estrogen production increases. However, molecular mechanisms explaining these conflicting phenomena remain unknown. Here, we showed that the pubertal sex hormone surge in female mice increases susceptibility to kidney ischemia reperfusion injury partly via downregulation of insulin-like growth factor 1 receptor (IGF-1R) expression in proximal tubules. Adult mice ovariectomized pre-pubertally (at postnatal day 21) showed strong tolerance to kidney ischemia, which was partly reversed by the administration of 17β-estradiol, while adult mice ovariectomized post-pubertally (at 8 weeks of age) were vulnerable to kidney ischemia. Kidney tubular IGF-1R protein expression decreased during postnatal growth but was highly expressed in adult mice ovariectomized pre-pubertally and in infant mice, which might be partly explained by different expression of an E3 ligase (MDM2) of IGF-1R. Mice deficient of Igf-1r in proximal tubules (iIGF-1RKO mice) during postnatal kidney growth showed increased susceptibility to ischemic injury. RNA-seq and western blotting analysis using proximal tubular cells from pre-pubertally ovariectomized iIGF-1RKO and control mice revealed altered expression of cell cycle-associated molecules such as cyclin D1. These results suggest that Igf-1r deletion during postnatal growth renders proximal tubular cells susceptible to ischemia possibly via altered cell cycle regulation. Thus, our findings provide evidence that exposure to pubertal sex hormones leads to increased susceptibility to kidney ischemia, which is partly mediated by modulation of IGF-1R signaling.

Intermittent preventive treatment for malaria in pregnancy and infant growth: a mediation analysis of a randomised trial

Intermittent preventive treatment for malaria in pregnancy (IPTp) can improve birth outcomes, but whether it confers benefits to postnatal growth is unclear. We investigated the effect of IPTp on infant growth in Uganda and its pathways of effects using causal mediation analyses. We analysed data from 633 infants born to mothers enrolled in a randomised trial of monthly IPTp with dihydroartemisinin-piperaquine (DP) vs. sulfadoxine-pyrimethamine (SP) (NCT02793622). Weight and length were measured from 0 to 12 months of age. Using generalised linear models, we estimated effects of DP vs. SP on gravidity-stratified mean length-for-age (LAZ) and weight-for-length Z-scores (WLZ). We investigated mediation by placental malaria, gestational weight change, maternal anaemia, maternal inflammation-related proteins, preterm birth, birth length, and birth weight. Mediation models adjusted for infant sex, gravidity, gestational age at enrolment, maternal age, maternal parasitaemia at enrolment, education, and wealth. SP increased mean LAZ by 0.18-0.28 Z from birth through age 4 months compared to DP, while DP increased mean WLZ by 0.11-0.28 Z from 2 to 8 months compared to SP among infants of multigravidae; at these ages, confidence intervals for mean differences excluded 0. We did not observe differences among primigravida. Mediators of SP included birth weight, birth length, maternal stem cell factor, and DNER. Mediators of DP included placental malaria and birth length, maternal IL-18, CDCP1, and CD6 at delivery. In high malaria transmission settings, this exploratory study suggests different IPTp regimens may influence infant growth among multigravidae, potentially through distinct pathways, in the exclusive breastfeeding period, when few other interventions are available. Stanford Center for Innovation in Global Health, Eunice Kennedy Shriver National Institute of Child Health and Human Development, Bill & Melinda Gates Foundation.

Late gestation maternal infection with bovine viral diarrhea virus impacts offspring feedlot performance, digestion, blood parameters, and hot carcass weights.

Fetal infection with bovine viral diarrhea virus (BVDV) after 150 d results in transient fetal infections (TI). Twenty-five unvaccinated, yearling Hereford heifers, seronegative for antibodies to BVDV1 and BVDV2, were bred by artificial insemination with X chromosome-bearing sperm from one Angus sire to examine the impact of TI on postnatal growth, estimated dry matter digestibility, blood parameters, and carcass characteristics. On d 175 of pregnancy, dams were intranasally inoculated with either sham control or 4.0 log median tissue culture infectious dose noncytopathic type2 BVDV to generate control or TI offspring, respectively. All control dams remained seronegative and all BVDV-inoculated dams seroconverted by d 14 post-inoculation. All control offspring were seronegative and all TI offspring were seropositive for antibodies to type 2 BVDV at birth. All offspring were raised on pasture until weaning. At weaning, all calves were transported to our research feedlot facility, housed in three pens, and transitioned to a high-energy concentrate-based diet. Heifer body weights (BW) and jugular blood samples were collected every 28 d. On d 84 of the feeding period, titanium dioxide was added to the diet of 12, age-paired, individually fed, heifers (6 control and 6 TI heifers; approximately 1 yr. of age) for 28 d and used to estimate dry matter digestibility. On d 105 and 240 ruminal fluid (approximately 900ml) was collected from every animal using a stomach pump and analyzed for short chain fatty acids (SCFA). After approximately 287 d on feed, heifers were transported to a USDA-inspected abattoir and harvested. TI heifers had lighter final BW (P < 0.04) when compared to control heifers. Average daily gain was greater (P < 0.01) in control compared to TI heifers. TI heifers had a 2.2% lesser (P < 0.05) apparent dry matter digestibility, lighter (P < 0.01) hot carcass weights, but similar ruminal SCFA compared to controls. Blood glucose concentrations were similar (P > 0.8) between control and TI heifers. Ceruloplasmin activity (P < 0.03) and the oxidized form of glutathione (GSSG; P < 0.01), indicators of chronic inflammation, were increased in plasma from TI heifers compared to controls. Other indicators of oxidative stress were not impacted (P > 0.10) by TI status. These data suggest that fetal BVDV transient infection negatively impacts growth throughout the feeding period, possibly by impacting gastrointestinal tract function and increasing systemic inflammation.

The Effects of War-Related Stress on Human Development: Differences in Body Proportions of Polish Women Born Before and During World War II.

This study aims to explore the lasting effects of stress experienced by pregnant women during World War II (WWII) on body and head measurements of their adult daughters. The research sample consists of 336 female university students born in Poland between 1925 and 1951. The data include body measurements and socioeconomic information (parental occupation and number of siblings) acquired from questionnaires collected between the 1950s and 1970s. Student's t-test, Mann-Whitney test and Analysis of Variance were used to analyze differences in body measurements between groups of women born before and during the war, as well as the possible influences of socioeconomic variables. The mean measurements of body height, symphysion height, and waist circumference were lower in women conceived and born during the war compared to those born in the pre-war period. In contrast, the mean measurements of biacromial (shoulder) width, trunk length, and three head dimensions were higher in women conceived and born during the war. Additionally, the number of siblings appeared to be a significant factor that may have influenced the body measurements of women in both groups. For instance, a higher number of living siblings, particularly sisters, was associated with reduced body dimensions, such as body height and waist circumference, while a greater number of deceased siblings was linked to an increase in certain body dimensions. The results suggest that war-related prenatal conditions may have influenced the postnatal growth and development of women conceived and born during the war. Notably, the direction of these changes varied, which indicates that the growth response to the war-related conditions was a complex adaptation, reflecting both positive and negative changes in different body parts, rather than a uniform pattern of growth suppression.

Editorial: Understanding the impact on metabolic health of interactions between pre- and post-natal nutrition, sex, growth and endocrine development

Editorial: Understanding the impact on metabolic health of interactions between pre- and post-natal nutrition, sex, growth and endocrine development

Preeclampsia and Future Implications on Growth and Body Composition in Preterm Infants

Background: Preeclampsia is associated with intrauterine growth restriction (IUGR), which can lead to impaired postnatal growth and neurodevelopment in preterm infants. Preeclampsia can also occur without IUGR and its impact on postnatal nutrition, growth, and body composition remains not fully investigated to the best of our knowledge. Methods: This study included infants born before 37 weeks of gestation who underwent air displacement plethysmography to measure body composition (fat-free mass [FFM] and fat mass [FM]) at term-equivalent age. We compared infants born to mothers with preeclampsia and IUGR (PE-IUGR group) and preeclampsia without IUGR (PE-non-IUGR group) to those born to mothers without preeclampsia (control group). Results: In total, 291 infants were enrolled (control: n = 227; PE-non-IUGR: n = 43; PE-IUGR: n = 21). FFM was significantly lower in the PE-IUGR (mean differences −231 g (IQR: (−373, −88); p &lt; 0.001)) and PE-non-IUGR groups (mean differences −260 g (IQR: (−372, −149); p &lt; 0.001)) in comparison to the control group. FM was not significantly different between the three groups. Conclusions: This study indicates that infants of preeclamptic mothers, even without IUGR, had significantly lower FFM at term-equivalent age compared to the control group. Further research is necessary to determine if these variations can be modified.

Widespread Gene Editing in the Brain via In Utero Delivery of mRNA Using Acid-Degradable Lipid Nanoparticles.

In utero gene editing with mRNA-based therapeutics has the potential to revolutionize the treatment of neurodevelopmental disorders. However, a critical bottleneck in clinical application has been the lack of mRNA delivery vehicles that can efficiently transfect cells in the brain. In this report, we demonstrate that in utero intracerebroventricular (ICV) injection of densely PEGylated lipid nanoparticles (ADP-LNPs) containing an acid-degradable PEG-lipid can safely and effectively deliver mRNA for gene editing enzymes to the fetal mouse brain, resulting in successful transfection and editing of brain cells. ADP-LNPs containing Cre mRNA transfected 30% of the fetal brain cells in Ai9 mice and had no detectable adverse effects on fetal development and postnatal growth. In addition, ADP-LNPs efficiently transfected neural stem and progenitor cells in Ai9 mice with Cre mRNA, which subsequently proliferated and caused over 40% of the cortical neurons and 60% of the hippocampal neurons to be edited in treated mice 10 weeks after birth. Furthermore, using Angelman syndrome, a paradigmatic neurodevelopmental disorder, as a disease model, we demonstrate that ADP-LNPs carrying Cas9 mRNA and gRNA induced indels in 21% of brain cells within 7 days postpartum, underscoring the precision and potential of this approach. These findings demonstrate that LNP/mRNA complexes have the potential to be a transformative tool for in utero treatment of neurodevelopmental disorders and set the stage for a frontier in treating neurodevelopmental disorders that focuses on curing genetic diseases before birth.

Distinguishing genetic alterations versus (epi)mutations in Silver-Russell syndrome and focus on the IGF1R gene.

Silver-Russell Syndrome (SRS) is a growth retardation disorder characterized by pre- and post-natal growth failure, relative macrocephaly at birth, prominent forehead, body asymmetry, and feeding difficulties. The main molecular mechanisms are imprinting alterations at multiple loci, though a small number of pathogenic variants have been reported in the SRS genes IGF2-PLAG1-HMGA2 and CDKN1C. However, around 40% of clinically suspected SRS cases do not achieve a molecular diagnosis, highlighting the necessity to uncover the underlying mechanism in unsolved cases. evaluate the frequency of genetic variants in undiagnosed SRS patients (NH-CSS≥4), and investigate whether (epi)genetic patients may be distinguished from genetic patients. 132 clinically SRS patients without (epi)genetic deregulations were investigated by Whole Exome (n=15) and Targeted (n=117) Sequencing. Clinical data from our cohort and from an extensive revision of literature were compared. pathogenic variants were identified in 9.1% of this cohort: 3% in IGF2, PLAG1, and HMGA2 genes, while 3% in the IGF1R gene, associated with IGF-1 resistance (IGF1RES), an SRS differential diagnosis. Overall, IGF2-PLAG1-HMGA2 and IGF1R account for 3.6% of SRS with NH-CSS score ≥ 4. A clinical cross-comparison of (epi)genetic versus genetic SRS underlined (epi)genotype-phenotype correlation, highlighted the prevalence of body asymmetry and relative macrocephaly in mosaic (epi)genetic SRS and recurrence of genetic familial cases. Furthermore, overlapping features were evidenced in (epi)genetic SRS and IGF1RES patients. Our study explores the frequency of genetic SRS, underscores body asymmetry as distinctive phenotype in (epi)genetic SRS and suggests IGF1R sequencing in SRS diagnostic flow-chart.

Sex-specific proximal tubular cell differentiation pathways identified by single-nucleus RNA sequencing

Postnatal kidney growth is substantial and involves expansion in kidney tubules without growth of new nephrons, which are the functional units of the kidney. Proliferation and differentiation pathways underpinning nephron elongation are not well defined. To address this, we performed sequential characterization of mouse kidney transcriptomics at the single cell level. Single nuclear RNA sequencing (snRNA-seq) was performed on kidney tissue from male and female mice at 1, 2, 4 and 12 weeks of age using the 10x Chromium platform. Unbiased clustering was performed on 68,775 nuclei from 16 animals. 31 discrete cellular clusters were seen, which were identified through comparison of their gene expression profiles to canonical markers of kidney cell populations. High levels of proliferation were evident at early time points in some cell types, especially tubular cells, but not in other cell types, for example podocytes. Proliferation was especially evident in Proximal Tubular Cells (PTCs) which are the most abundant cell type in the adult kidney. Uniquely when compared to other kidney cell types, PTCs demonstrated sex-specific expression profiles at late, but not early, time points. Mapping of PTC differentiation pathways using techniques including trajectory and RNA Velocity analyses delineated increasing PTC specialization and sex-specific phenotype specification. Our single-cell transcriptomics data characterise cellular states observed during kidney growth. We have identified PTC differentiation pathways that lead to sex-specific tubular cell phenotypes. Tubular proliferative responses are of central importance in postnatal kidney growth and have also been linked to kidney recovery versus fibrosis following injury. Our unbiased and comprehensive dataset of tubular cell development can be used to identify candidate pathways for therapeutic targeting.

Early human milk feeding: Relationship to intestinal barrier maturation and postnatal growth.

Early exposure to mother's own milk (MOM) promotes intestinal barrier maturation in preterm infants. We hypothesized (1) donor human milk (DHM) supplementation reduces intestinal permeability (IP) similar to exclusive MOM and (2) early HM exposure and low IP at 7-10 days postnatal age (PNA) are associated with improved growth outcomes. IP was measured by the standard sugar absorption test (SAT) in infants <33 weeks gestation between 7-10 days PNA. Nutritional and anthropometric data were recorded. Postnatal growth failure (PNGF) was defined as a decrease in weight z-score >1 from birth to discharge to home. Of 158 preterm infants, the mean (SD) gestational age was 29.9(2.3) weeks and birthweight 1388(424) g. Diet prior to SAT was exclusive MOM [N = 55(35%)], DHM ± MOM [N = 52(33%)], or preterm formula±MOM [N = 51(32%)]. The mean Lactulose(La)/Rhamnose(Rh) ratio was lower in the exclusive MOM [0.06(0.07)] and DBM ± MOM [0.05(0.07)] groups compared to the preterm formula±MOM group [0.11(0.11)], p < 0.01). Cumulative intake >150 ml/kg MOM ± DHM, but not preterm formula within 7-10 days PNA was associated with early intestinal barrier maturation. Low IP was not associated with lower risk of PNGF at discharge. Low IP is associated with cumulative intake of MOM alone or supplemented with DHM > 150 ml/kg within 7-10 days PNA. Clinicaltrials.gov NCT01756040 ; web link to study on registry: https://clinicaltrials.gov/study/NCT01756040 . Key message Early intestinal barrier maturation is associated with cumulative intake of exclusive MOM alone or supplemented with DHM > 150 ml/kg within 7-10 days after birth, but is not associated with lower risk of PNGF at time of discharge. What it adds to existing literature? This observational study is the first study to demonstrate that supplemental DHM promotes intestinal barrier maturation similar to MOM alone. What is the impact? The findings underscore the importance of early introduction of human milk feeds as MOM or MOM supplemented with DHM in sufficient volume to promote early intestinal barrier maturation.

Type-H endothelial cell protein Clec14a orchestrates osteoblast activity during trabecular bone formation and patterning

Type-H capillary endothelial cells control bone formation during embryogenesis and postnatal growth but few signalling mechanisms underpinning this influence have been characterised. Here, we identify a highly expressed type-H endothelial cell protein, Clec14a, and explore its role in coordinating osteoblast activity. Expression of Clec14a and its ligand, Mmrn2 are high in murine type-H endothelial cells but absent from osteoblasts. Clec14a−/− mice have premature condensation of the type-H vasculature and expanded distribution of osteoblasts and bone matrix, increased long-bone length and bone density indicative of accelerated skeletal development, and enhanced osteoblast maturation. Antibody-mediated blockade of the Clec14a-Mmrn2 interaction recapitulates the Clec14a−/− phenotype. Endothelial cell expression of Clec14a regulates osteoblast maturation and mineralisation activity during postnatal bone development in mice. This finding underscores the importance of type-H capillary control of osteoblast activity in bone formation and identifies a novel mechanism that mediates this vital cellular crosstalk.

Neurodevelopmental Changes and Postnatal Growth in the First 3 Years of Extremely Preterm Infants

Introduction: Infants born extremely preterm are at high risk for neurodevelopmental problems. However, their neurodevelopment exhibits a variety of trajectories. This study aimed to investigate the association between changes in neurodevelopmental outcomes and clinical characteristics among extremely preterm infants. Methods: This is a retrospective study of surviving children born at gestational age 22–28 weeks in Kyushu University Hospital between 2010 and 2020. We collected perinatal and post-discharge data and investigated the association between clinical characteristics and changes in developmental quotient (DQ) scores between 1.5 and 3 years of corrected age. Results: Out of the 179 eligible extremely preterm infants, 115 (64%) underwent neurological evaluations at 1.5 and 3 years of corrected age. Among them, 33 (29%) showed improvement in their DQ scores (+10 or more), 62 (54%) showed no change (−9 to +9), and 20 (17%) showed a decline (−10 or less). Gestational age, birth weight, and perinatal complications during the NICU stay did not affect individual changes in DQ scores. Multivariable analysis revealed that greater growth in height until age 3 years was a significant predictor of increasing DQ scores, while male sex and having siblings had a negative effect on changes in the DQ scores. Conclusion: We first demonstrate clinical data conceptualizing that growth in height, sex, and sibling status, rather than perinatal complications, are biologically linked with favorable or unfavorable neurodevelopmental changes of extremely preterm infants during the first 3 years of life.

SRSF1 Is Crucial for Maintaining Satellite Cell Homeostasis During Skeletal Muscle Growth and Regeneration.

The splicing factor SRSF1 emerges as a mater regulator of cell proliferation, displaying high expression in actively proliferative satellite cells (SCs). In SRSF1 knockout mice (KO) generated via MyoD-Cre, early mortality and muscle atrophy are observed during postnatal muscle growth. Despite these findings, the precise mechanisms through which SRSF1 loss influences SCs' functions and its role in muscle regeneration remain to be elucidated. To unravel the exact mechanisms underlying the impact of SRSF1 deficiency SC functions, we employed single-cell RNA sequencing (scRNA-seq) on a mononuclear cell suspension isolated from the newborn diaphragm of KO and control mice. Concurrently, we subjected diaphragm muscles to RNA-seq analysis to identify dysregulated splicing events associated with SRSF1 deletion. For the analysis of the effect of SRSF1 deletion on muscle regeneration, we generated mice with inducible SC-specific Srsf1 ablation through Pax7-CreER. SRSF1 ablation was induced by intraperitoneal injection of tamoxifen. Using cardiotoxin-induced muscle injury, we examined the consequences of SRSF1 depletion on SC function through HE staining, immunostaining and EdU incorporation assay. C2C12 myoblasts and isolated myoblasts were employed to assess stem cell function and senescence. Utilizing scRNA-seq analysis, we observed a noteworthy increase in activated and proliferating myoblasts when SRSF1 was absent. This increase was substantial, with the proportion rising from 28.68% in the control group to 77.06% in the knockout group. However, these myoblasts experienced mitotic abnormalities in the absence of SRSF1, resulting in cell cycle arrest and the onset of cellular senescence. In the knockout mice, the proportion of Pax7+ cells within improper niche positioning increased significantly to 25% compared to 12% in the control cells (n ≥ 10, p < 0.001). Furthermore, there was an observation of persistent cell cycle exit specifically in the Pax7+ cells deficient in SRSF1 (n = 6, p < 0.001). SRSF1 plays a pivotal role in regulating the splicing of Fgfr1op2, favouring the full-length isoform crucial for mitotic spindle organization. Disrupting SRSF1 in C2C12 and primary myoblasts results in multipolar spindle formation (p < 0.001) and dysregulated splicing of Fgfr1op2 and triggers cellular senescence. Consequently, adult SCs lacking SRSF1 initially activate upon injury but face substantial challenge in proliferation (n = 4, p < 0.001), leading to a failure in muscle regeneration. SRSF1 plays a critical role in SCs by ensuring proper splicing, maintaining mitotic progression and preventing premature senescence. These findings underscore the significant role of SRSF1 in controlling SC proliferation during skeletal muscle growth and regeneration.

Impact of postpartum physical activity on cardiometabolic health, breastfeeding, injury and infant growth and development: a systematic review and meta-analysis

ObjectiveTo examine the relationship between postpartum physical activity and maternal postnatal cardiometabolic health, breastfeeding, injury, and infant growth and development.DesignSystematic review with random-effects meta-analysis and meta-regression.Data sourcesEight online databases were...

6509 IGF-1 receptor and insulin receptor in LepRb neurons coordinates body growth, reproduction, and metabolism

Abstract Disclosure: M. Wang: None. J.W. Hill: None. Growth and reproduction are tightly linked. Growth hormone (GH) deficiency results in a profound suppression of postnatal growth accompanied by severely delayed puberty and reproductive senescence, while GH excess is correlated with the reverse. The specific mechanism underlying this delay is undefined. Although leptin receptor (LepRb)-expressing neurons are known to link body growth and reproduction, the role of insulin-like growth factor 1 receptor (IGF1R) signaling in LepRb neuron function is unknown. Previous studies have shown that IGF-1 and insulin can bind to each other’s receptor, permitting IGF-1 signaling in the absence of IGF1R. Therefore, we created mice lacking IGF1R exclusively in LepRb neurons (IGF1RLepRb mice) and mice simultaneously lacking IGF1R and IR in LepRb neurons (IGF1R/IRLepRb mice) to test if IGF1R and insulin receptor (IR) cooperatively regulate metabolic and reproductive functions. IGF1RLepRb and IGF1R/IRLepRb mice displayed delayed onset of puberty and impaired fertility in both sexes, which suggested that both IGF1R and IR in LepRb neurons are required for normal reproduction. Additionally, we found transient growth retardation in IGF1RLepRb and IGF1R/IRLepRb mice. Loss of IGF1R in LepRb neurons led to lower serum IGF-1 and GH levels in male mice and impaired trabecular and cortical bone development in mice of both sexes. Only transient and mild changes were noticed in the body weight. However, we found IGF1R and IR in LepRb neurons jointly regulate body mass composition, energy homeostasis and glucose homeostasis, as shown by elevated fat mass composition, low energy expenditure and low physical activity in IGF1R/IRLepRb mice. Taken together, these studies identify the unique and cooperative role of LepRb IGF1R and IRs in the regulation of body growth, reproduction, and metabolism. Presentation: 6/3/2024

8134 Hypothalamic Dlk1 Expression is Not Essential for Preventing Early Maturation of the Reproductive Axis in Female and Male Mice

Abstract Disclosure: D.B. Macedo: None. H. Kim Kyeol: None. A. Abreu: None. A. Latronico: None. R.S. Carroll: None. U.B. Kaiser: None. Background and Objectives: Inactivating mutations in Delta-like homolog 1 (DLK1), a maternally imprinted gene on chromosome 14, have been recognized as a genetic cause of central precocious puberty (CPP) in humans. It is well established that the timing of puberty, especially in females, is highly sensitive to energy stores and metabolic cues, with lower body fat negatively correlated with age at puberty and menarche. Mice lacking Dlk1 have pre- and postnatal growth retardation. Despite their considerably lower body weight (BW), we found that Dlk1 deficient females achieved puberty at the same age as controls (‘relative precocious puberty’). Moreover, Dlk1 deficiency led to activation of the reproductive axis despite lower levels of kisspeptin and leptin, an adipose tissue hormone with a permissive/stimulatory effect on metabolic control of reproduction. Dlk1 is a transmembrane protein that plays an essential role in inhibiting adipocyte differentiation and its biologically active form is soluble. Increased hypothalamic expression postnatally suggests a neuroendocrine function, but the precise mechanism by which DLK1 deficiency leads to CPP is yet to be deciphered. In this study, we aimed to investigate the role of hypothalamic Dlk1 expression on pubertal onset without the interference of diminished BW, using a conditional knockout (cKO) mouse model. Methods and Results: We generated a targeted Dlk1 knockout mouse model by crossing mice expressing Cre recombinase under the control of Nestin gene (Nes Cre), expressed primarily in neuro-epithelial cells, with mice harboring the Dlk1 gene flanked by loxP sites (Dlk1fl). Since Dlk1 is imprinted and expressed only by the paternal allele, we bred heterozygous Dlk1fl/+ male mice with Nes Cre females to obtain Dlk1fl/Cre (Dlk1 cKO), Dlk1+/Cre (Nes Cre) and Dlk1+/+ (wild type - WT). We confirmed by RT-qPCR that Dlk1 mRNA was undetectable in the mediobasal hypothalamus of Dlk1 cKO adult male mice, whereas it was present in Nes Cre and WT mice. We noted a lower BW in Nes Cre compared to WT mice, as previously reported. However, no difference in BW was observed between Dlk1 cKO and Nes Cre mice at the timing of puberty (females: Dlk1 cKO 12.6 ± 0.8 g vs. Nes Cre 13.8 ± 0.2 g, P = 0.18; males: Dlk1 cKO 12.4 ± 0.2 g vs. Nes Cre 13.1 ± 0.5 g, P = 0.26). Puberty onset, assessed by age at vaginal opening (females) and at preputial separation (males), was not affected by hypothalamic Dlk1 deletion (Dlk1 cKO: 35.6 ± 2.7 days vs. Nes Cre 34.6 ± 0.7 days, P = 0.73; Dlk1 cKO 29.0 ± 0.6 vs. Nes Cre: 30.3 ± 0.6 days, P = 0.19). Conclusion: In contrast to global Dlk1 deficiency, targeted deletion of Dlk1 from neuronal and glial cells did not affect body weight or timing of pubertal onset. These findings suggest that Dlk1 originates from peripheral tissues, such as adipocytes, to regulate reproduction and metabolism. Presentation: 6/1/2024

Molecular diagnosis of patients with syndromic short stature identified by trio whole-exome sequencing.

Short stature is a complex disorder with phenotypic and genetic heterogeneity. This study aimed to investigate clinical phenotypes and molecular basis of a cohort of patients with short stature. Trio whole-exome sequencing (Trio-WES) was performed to explore the genetic aetiology and obtain a molecular diagnosis in twenty Chinese probands with syndromic and isolated short stature. Of the twenty probands, six (6/20, 30%) patients with syndromic short stature obtained a molecular diagnosis. One novel COMP pathogenic variant c.1359delC, p.N453fs*62 and one LZTR1 likely pathogenic variant c.509G>A, p.R170Q were identified in a patient with short stature and skeletal dysplasia. One novel de novo NAA15 pathogenic variant c.63T>G, p.Y21X and one novel de novo KMT2A pathogenic variant c.3516T>A, p.N1172K was identified in two probands with short stature, intellectual disability and abnormal behaviours, respectively. One patient with short stature, cataract, and muscle weakness had a de novo POLG pathogenic variant c.2863T>C, p.Y955H. One PHEX pathogenic variant c.1104G>A, p.W368X was identified in a patient with short stature and rickets. Maternal uniparental disomy 7 (mUPD7) was pathogenic in a patient with pre and postnatal growth retardation, wide forehead, triangular face, micrognathia and clinodactyly. Thirteen patients with isolated short stature had negative results. Trio-WES is an important strategy for identifying genetic variants and UPD in patients with syndromic short stature, in which dual genetic variants are existent in some individuals. It is important to differentiate between syndromic and isolated short stature. Genetic testing has a high yield for syndromic patients but low for isolated patients.