Physiological genomics最新文献

{"title":"Dissecting the interplay between estrogen- and diet-induced obesity on the gut microbiota.","authors":"Samuel D Walton, Justine M Abais-Battad","doi":"10.1152/physiolgenomics.00338.2025","DOIUrl":"10.1152/physiolgenomics.00338.2025","url":null,"abstract":"","PeriodicalId":20129,"journal":{"name":"Physiological genomics","volume":" ","pages":"179-180"},"PeriodicalIF":2.5,"publicationDate":"2026-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13094944/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147474990","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The athlete microbiome project: integrating deep learning to reveal microbial associations of physical fitness.","authors":"Garry S Lewis, Samson Adejumo, Sebastian Reczek, Judy Malas, Karolis Ramanauskas, Joseph F Walker, Marc D Cook, Craig A Horswill, Jarrad Hampton-Marcell","doi":"10.1152/physiolgenomics.00278.2025","DOIUrl":"10.1152/physiolgenomics.00278.2025","url":null,"abstract":"<p><p>Regular physical training improves human fitness and health through direct effects on muscle and metabolism and indirect effects via alterations in gut microbiome composition. To determine whether athletes harbor a distinct gut microbiome and whether microbiome composition associates with established markers of physical fitness, maximum oxygen uptake (Vo_2max) and percent fat-free mass, we conducted a secondary analysis of amplicon sequencing data and metadata from published human microbiota studies across three continents. Participants were categorized as athletes (<i>n</i> = 656) or nonathletes (<i>n</i> = 199). Using multivariate statistics, random forest models, and a multilayer perceptron neural network, we identified structured differences in gut microbiome composition associated with fitness metrics and athletic status. Random forest regression models explained up to 63% of the variance in percent fat-free mass and 45% in Vo_2max, with taxa such as <i>Faecalibacterium</i>, <i>Megamonas</i>, <i>Bifidobacterium</i>, and <i>Blautia</i> ranking among the most informative predictive features across analyses. Classification models further demonstrated that athletic status could be predicted from microbiome composition: a mixed-effects-informed random forest achieved a balanced accuracy of 71%, whereas a multilayer perceptron captured coordinated, multivariate microbial patterns and achieved stable performance across stratified fivefold cross-validation and an independent held-out test set comprising 20% of samples not used during model training [balanced accuracy = 0.91; area under the receiver operating characteristic curve (AUC) = 0.97]. Together, these findings indicate that athletic status and fitness-related traits are associated with gut microbiome compositional patterns, highlighting candidate taxa for mechanistic validation and demonstrating the utility of integrative machine learning for distinguishing athletes from nonathletes.<b>NEW & NOTEWORTHY</b> From 855 gut microbiome samples spanning three continents, we identify microbial patterns associated with athletic status and physical fitness. We show that athletic status can be predicted from microbiome signatures [balanced accuracy ≈ 91%; area under the receiver operating characteristic curve (AUC) = 0.97]. Key taxa identified across models were linked to maximum oxygen uptake (Vo_2max) and % fat-free mass, highlighting multivariate microbiome features relevant to human performance.</p>","PeriodicalId":20129,"journal":{"name":"Physiological genomics","volume":" ","pages":"199-211"},"PeriodicalIF":2.5,"publicationDate":"2026-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147575195","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Nuclear receptor subfamily 4 group a member 2 induces a Warburg-like effect and promotes phospholipids synthesis in the mouse heart.","authors":"Sadia Ashraf, Dorcas Odogwu, David D McPherson, Romain Harmancey","doi":"10.1152/physiolgenomics.00319.2025","DOIUrl":"10.1152/physiolgenomics.00319.2025","url":null,"abstract":"<p><p>Myocardial metabolic flexibility is critical to ensuring the heart's capacity to maintain contraction and cellular functions under rapidly evolving environmental conditions. Although it is a tightly regulated process, loss of metabolic flexibility is often regarded as a contributing factor to heart failure. This study aims to determine the effects of the early response transcription factor nuclear receptor subfamily 4 group A member 2 (NR4A2) on cardiac metabolism and the resulting impact on left ventricular function. A multiomics approach combining the analysis of global ventricular gene expression, genome-wide NR4A2 binding, and untargeted metabolomics was used to track the molecular effects of cardiomyocyte-specific NR4A2 activation in male and female mice over time. Doppler echocardiography was performed in parallel to monitor changes in left ventricular function. We found that NR4A2 acts as a direct transcriptional activator of the genes encoding the glucose transporter type 4 and most glycolytic enzymes. The upregulation of glycolysis was accompanied by the inhibition of fatty acid β-oxidation and by activation of glutamine-dependent reductive carboxylation to promote the synthesis of phospholipids. This was further supported by NR4A2-dependent transcriptional regulation of key enzymes in the phosphatidic acid pathway. Rewiring of the Krebs cycle for biosynthetic purposes was followed by a progressive decline in left ventricular contractility. In conclusion, our results expose NR4A2 as a critical component of the cell regulatory machinery governing transcriptional reprogramming of cardiac metabolism under stress. These findings provide a conceptual framework illustrating how an acute adaptive metabolic response may become maladaptive on the long-term.<b>NEW & NOTEWORTHY</b> The plasticity of myocardial metabolism is regulated by a poorly understood network of transcription factors. We show that stress-activated nuclear receptor NR4A2 is a potent transcriptional activator of glycolysis in the mouse heart. Prolonged NR4A2 activation triggers a switch from oxidative to biosynthetic metabolism, accompanied by a progressive decline in left ventricular contractility. These findings provide a conceptual framework illustrating how an acute adaptive metabolic response may become maladaptive in the long-term.</p>","PeriodicalId":20129,"journal":{"name":"Physiological genomics","volume":" ","pages":"181-194"},"PeriodicalIF":2.5,"publicationDate":"2026-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13078181/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147378323","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Epigenetic signatures and genetic variants associated with muscle strength in postmenopausal women: potential bone muscle cross talk via BMP1 mechanisms.","authors":"Guilherme da Silva Rodrigues, Natalia Yumi Noronha, Jonas Benjamim, Andressa Crystine da Silva Sobrinho, Ivo Vieira de Sousa Neto, Chanachai Sae-Lee, Pitaksin Chitta, Takuji Kawamura, Fernando Barbosa, Carla B Nonino, Lígia Moriguchi Watanabe, Carlos Roberto Bueno","doi":"10.1152/physiolgenomics.00254.2025","DOIUrl":"10.1152/physiolgenomics.00254.2025","url":null,"abstract":"<p><p>Muscle strength decline is a hallmark of aging and contributes to frailty and bone deterioration, yet the genomic and epigenomic mechanisms predicting functional strength remain unclear. We applied a multiomics approach to identify genetic and epigenetic signatures of muscle strength variability in postmenopausal women. A total of 141 women aged 50-70 yr underwent functional tests, biochemical analysis, anthropometry, blood pressure assessment, and dual-energy X-ray absorptiometry. Participants were classified into higher- and lower-strength groups based on validated upper and lower limb tests. Genome-wide genotyping was performed with the Illumina Global Screening Array, and DNA methylation was measured using the Illumina EPIC 850 K array. A polygenic risk score (PRS) was generated in a training cohort (<i>n</i> = 100) and validated in an independent group (<i>n</i> = 41). Epigenetic scores (EpiScores) were calculated using MethylDetectR, and four fitness-related epigenetic clocks (DNAmGrip, DNAmGait, DNAmVO2max, and DNAmFitAge) were derived with the methylclock package. Twelve single-nucleotide polymorphisms (SNPs) were associated with strength phenotypes, and the PRS predicted group classification with 51.2% accuracy. Epigenetic analysis revealed 12 differentially methylated regions, including higher bone morphogenetic protein 1 (BMP1) EpiScore levels in women with greater strength. Functional enrichment indicated pathways related to bone remodeling and vascular regulation. In the lower strength group, BMP1 EpiScore correlated inversely with femoral neck T-score (<i>r</i> = -0.66, <i>P</i> = 0.037). A meta-analysis of public muscle transcriptomes showed that resistance training increases BMP1 expression. These findings highlight molecular mechanisms linking genetic and epigenetic variation to musculoskeletal aging and functional decline in postmenopausal women.<b>NEW & NOTEWORTHY</b> This study integrates genome-wide genotyping, DNA methylation, and transcriptomic validation to reveal genetic and epigenetic determinants of muscle strength in postmenopausal women. We identify novel SNPs, a predictive polygenic risk score, and higher BMP1 epigenetic scores linked to greater muscle strength and bone remodeling pathways. These multiomics insights provide potential biomarkers for musculoskeletal aging and targets for strategies to preserve strength and skeletal health in older women.</p>","PeriodicalId":20129,"journal":{"name":"Physiological genomics","volume":" ","pages":"152-169"},"PeriodicalIF":2.5,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146113919","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Monitored food intake in early pregnancy modulates the maternal microbiome in the obese BPH/5 mouse model of superimposed preeclampsia.","authors":"Kelly Fan, Chin-Chi Liu, Kalie F Beckers, Christopher J Schulz, Gary W Childers, Jenny L Sones","doi":"10.1152/physiolgenomics.00213.2025","DOIUrl":"10.1152/physiolgenomics.00213.2025","url":null,"abstract":"<p><p>Preeclampsia (PE) is a life-threatening pregnancy disorder strongly associated with maternal obesity, yet the mechanistic links between diet, microbiome, and disease risk remain unclear. The obese BPH/5 mouse, which spontaneously develops PE-like features, provides a model to investigate how maternal nutrition influences microbial and metabolic profiles. Here, we tested the effects of modest caloric restriction [pair-fed (PF)] initiated at <i>embryonic day 0.5</i> (e0.5) on maternal microbiota and circulating metabolites at <i>embryonic day 7.5</i> (e7.5). Microbial communities were profiled by 16S rRNA sequencing across fecal, oral, and vaginal niches, and serum short-chain fatty acids (SCFAs) were quantified by gas chromatography mass spectrometry. The PF BPH/5 dams exhibited a markedly reduced Firmicutes-to-Bacteroidetes ratio and increased abundance of <i>Bacteroides</i> and <i>Lactobacillus</i> in fecal samples, which are taxa associated with improved metabolic balance and gut barrier support. In contrast, PF increased Proteobacteria abundance in BPH/5 vaginal and oral sites, a shift linked to inflammation and barrier dysfunction. Serum acetic acid was significantly decreased in PF BPH/5 dams and their offspring, suggesting that restricted intake lowers systemic SCFA availability. These findings demonstrate that early pregnancy caloric restriction produces both beneficial and adverse microbial shifts, suggesting that high-fiber dietary interventions that enhance SCFA production may better support maternal-fetal health than caloric restriction alone.<b>NEW & NOTEWORTHY</b> Caloric restriction via monitored food intake in early pregnancy reshaped the maternal microbiome in obese BPH/5 mice, lowering fecal F/B ratios and enriching <i>Bacteroides</i> and <i>Lactobacillus</i>, while simultaneously reducing systemic acetic acid and increasing Proteobacteria in vaginal and oral sites. These findings reveal that diet-microbiome interactions in early gestation exert both beneficial and detrimental effects, underscoring the need for alternative interventions, potentially high-fiber, to support SCFA production and maternal-fetal health.</p>","PeriodicalId":20129,"journal":{"name":"Physiological genomics","volume":" ","pages":"144-151"},"PeriodicalIF":2.5,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13078920/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146043528","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Systems genomics reveals age- and sex-dependent metabolic dysregulation from <i>Glo1</i> reduction in mice.","authors":"Ingrid Cely, Montgomery Blencowe, Le Shu, Graciel Diamante, In Sook Ahn, Guanglin Zhang, Jonnby LaGuardia, Ruoshui Liu, Owen Briscoe, Zara Saleem, Susanna Wang, Richard C Davis, Hongxiu Qi, Aldons J Lusis, Xia Yang","doi":"10.1152/physiolgenomics.00106.2025","DOIUrl":"10.1152/physiolgenomics.00106.2025","url":null,"abstract":"<p><p>Glyoxalase 1 (Glo1) detoxifies reactive dicarbonyl compounds such as methylglyoxal, a precursor of advanced glycation end products (AGEs), which contribute to metabolic disorders. However, the contribution of AGE-independent mechanisms to <i>Glo1</i>-related metabolic dysfunction remains unclear. We conducted a longitudinal study in male and female <i>Glo1</i> heterozygous knockdown (<i>Glo1</i>^+/-) mice (∼50% <i>Glo1</i> expression). Metabolic phenotypes, including body weight, adiposity, glycemic control, and plasma lipid levels, were assessed over time. Atherosclerotic burden, AGE levels, and gene expression profiles in liver, adipose, muscle, kidney, and aorta were examined to identify pathway alterations and regulatory genes affected by <i>Glo1</i> reduction. Partial <i>Glo1</i> loss resulted in obesity, hyperglycemia, dyslipidemia, and altered lipid metabolism in an age- and sex-dependent manner, with most phenotypes emerging after ∼14 wk. <i>Glo1</i>^+/- females exhibited impaired glycemic control and elevated triglycerides, along with perturbations in adipogenesis, peroxisome proliferator-activated receptor-γ (PPARγ) signaling, insulin signaling, and fatty acid metabolism in liver and adipose tissue. <i>Glo1</i>^+/- males displayed increased skeletal muscle mass and visceral adiposity with changes in lipid metabolic pathways. Methylglyoxal-derived AGE accumulation was altered only in male skeletal muscle and did not explain broader phenotypes. Transcriptomic analyses suggest that altered glucose and lipid metabolism may be partially driven by the alternative detoxification of methylglyoxal to metabolites such as pyruvate. Transcription factor analysis identified <i>Hnf4a</i> (across tissues) and <i>Arntl</i> (in aorta, liver, and kidney) as female-biased regulators altered by <i>Glo1</i> deficiency. <i>Glo1</i> reduction disrupts metabolic health through sex- and age-dependent pathways largely independent of AGE accumulation, involving tissue-specific metabolic reprogramming and transcriptional regulation.<b>NEW & NOTEWORTHY</b> This study reveals that partial deficiency of glyoxalase 1 (Glo1) leads to age- and sex-specific metabolic dysfunction in mice through transcriptional and regulatory changes independent of advanced glycation end products (AGEs). Transcriptomic profiling and integrative genomics identified female-biased transcription factors and genome-wide association study (GWAS)-linked metabolic genes as key mediators. These findings uncover novel, AGE-independent regulatory pathways linking Glo1 to metabolic disease risk and emphasize the importance of sex-specific analysis in metabolic genomics research.</p>","PeriodicalId":20129,"journal":{"name":"Physiological genomics","volume":" ","pages":"125-143"},"PeriodicalIF":2.5,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12928164/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145990247","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Changes in the saliva metabolome occur very rapidly in response to acute physical stress.","authors":"Alexandra M Niclou, Meaghan E Beckner, Jesse A Stein, Joseph J Knapik, Tracey J Smith, Lee M Margolis, Drew Van Dam, Nicholas D Barringer, Matthew Larsen, Harris R Lieberman","doi":"10.1152/physiolgenomics.00197.2025","DOIUrl":"10.1152/physiolgenomics.00197.2025","url":null,"abstract":"<p><p>Saliva metabolomics can detect change over time in the metabolic response to physical stress including sustained military training. Whether saliva metabolomics can provide insight into the effects of acute stress, such as a brief hand-to-hand combat match, on metabolic function is not known. This study characterizes changes in saliva metabolome at rest, before, and immediately following a brief, but high-stress hand-to-hand combat event, among West Point Cadets. Cadets (<i>N</i> = 60, 21 ± 1 yr, 77 ± 14 kg, 16 females) provided saliva samples at the beginning of a hand-to-hand combat course under rested conditions (baseline), and after 3 mo of training immediately before (prefight) and after (postfight) the final, 3-min match of the course. Salivary samples were analyzed with global metabolomics profiling. MetaboAnalyst 6.0 was used to detect changes in metabolites between time points. Of the 406 analyzable metabolites detected, none significantly differed between baseline and prefight. At postfight, 81 metabolites increased and 2 decreased by greater than or equal to twofold compared with prefight. Changes in metabolites were primarily related to carbohydrate (19%), lipid (27%), and amino acid (34%) metabolism, specifically glutamate and histidine metabolism, suggesting a rapid increase in energy availability. Saliva metabolomics successfully identified significant changes in metabolism in response to a brief hand-to-hand combat match, demonstrating rapid increases in energy availability in response to an acute physical stress event.<b>NEW & NOTEWORTHY</b> Using salivary metabolomics, the present study captured rapid physiological changes in amino acid and lipid metabolites following a ≤3-min hand-to-hand combat event in military Cadets. Saliva metabolomics is a rapid, noninvasive method to capture metabolomic changes in brief athletic events and provides insight into substrate utilization of individuals in response to brief, acute physical stress.</p>","PeriodicalId":20129,"journal":{"name":"Physiological genomics","volume":" ","pages":"170-178"},"PeriodicalIF":2.5,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146150230","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Transcriptomics and metabolomics analysis reveal cell subpopulations of trophoblast cells associated with preeclampsia.","authors":"Xiaojun Zhu, Ying Jiang, Lilin Wang, Peiyue Jiang, Zixing Zhong, Hetong Li, Caihong Zheng, Lujiao Chen, Juan Wei, Xishi Lin, Peng Ding, Zehua Dong, Xiaosheng Wang, Qiong Luo","doi":"10.1152/physiolgenomics.00185.2025","DOIUrl":"10.1152/physiolgenomics.00185.2025","url":null,"abstract":"<p><p>Placental abnormalities are central to preeclampsia (PE), yet the cellular and molecular mechanisms underlying this dysfunction remain unclear. We applied a multi-layered, integrative approach to investigate placental tissue from patients with PE and matched controls. Single-cell RNA sequencing (scRNA-seq; GSE173193) and bulk RNA sequencing (bulk RNA-seq; GSE203507) datasets were obtained from the Gene Expression Omnibus. The scRNA-seq dataset included two PE and two control samples, whereas the bulk RNA-seq dataset focused on eight early-onset PE and five uncomplicated term births. Trophoblast subpopulations were identified via scRNA-seq, and pseudotime analysis was used to trace differentiation trajectories. Differential expression and pathway enrichment analyses were performed to elucidate molecular alterations. For metabolomic profiling, plasma samples from six patients with PE and six controls (3 replicates each) were analyzed. Transcriptomic and metabolomic data were integrated to investigate gene-metabolite interactions and their relevance to PE pathogenesis. Villous cytotrophoblasts (VCTs) and syncytiotrophoblasts (SCTs) were more abundant in PE placentas, whereas extravillous trophoblasts (EVTs) were reduced compared with controls. Five trophoblast subpopulations-SCT-VCT, Mix, EVT, VCT, and SCT-were characterized by distinct marker genes. Pseudotime analysis indicated differentiation from mixed states toward specific trophoblast lineages. Immune-related pathways were significantly enriched in PE. Integrated analysis highlighted key connections between metabolites, gene expression, and PE-related pathways, implicating oxidative stress, inflammation, metabolic dysregulation, and vascular dysfunction. Our study provides novel insights into placental dysfunction in PE, highlighting alterations in trophoblast subpopulations and immune pathways. These findings may inform strategies for early diagnosis, prevention, and therapeutic intervention in PE.<b>NEW & NOTEWORTHY</b> Our integrative multi-omics approach, spanning single-cell, bulk transcriptomic, and targeted metabolomic data, demonstrates convergent cellular and metabolic abnormalities in preeclampsia. We find disrupted trophoblast composition, altered differentiation patterns, and metabolic pathway shifts that jointly distinguish preeclamptic placentas from controls. These results advance understanding of placental dysfunction and underscore the value of multi-omics strategies for dissecting complex pregnancy disorders.</p>","PeriodicalId":20129,"journal":{"name":"Physiological genomics","volume":" ","pages":"89-100"},"PeriodicalIF":2.5,"publicationDate":"2026-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145775213","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Multiomics alterations associated with tolerance and response to simulated progressive hemorrhage in healthy adult humans.","authors":"Burook Misganaw, Seid Muhie, Aarti Gautam, Stacy-Ann Miller, Ida Nela Crespo Rosales, George I Dimitrov, Bintu Sowe, Christopher P Johnson, Shelly K Roberts, Riley J Regimbal, Chad C Wiggins, Michael J Joyner, Timothy B Curry, Victor A Convertino, Rasha Hammamieh","doi":"10.1152/physiolgenomics.00253.2025","DOIUrl":"10.1152/physiolgenomics.00253.2025","url":null,"abstract":"<p><p>Hemorrhagic shock is a leading cause of preventable death among military and civilian trauma patients. Although caused by severe hypovolemia, the threshold of blood volume reduction that triggers recruitment of compensatory mechanisms varies markedly. Individuals have been classified as having low tolerance (LT) or high tolerance (HT) to hypovolemia; however, molecular features contributing to tolerance remain unclear. Here we investigate multiomics correlates of hypovolemia tolerance and molecular responses underlying physiological compensating mechanisms of blood loss. Healthy adult human subjects (<i>n</i> = 133) recruited from two sites underwent lower body negative pressure (LBNP) to simulate progressive hemorrhage. The primary outcome variable was hemodynamic instability accompanied by onset of decompensated shock defined by systolic blood pressure <80 mmHg. Participants were classified into HT (<i>n</i> = 90) and LT (<i>n</i> = 43) subjects using a cumulative stress index quantifying maximal LBNP tolerance. Genome-wide messenger ribonucleic acid (mRNA), microRNA, whole exome sequencing, and select protein abundances were assayed using blood samples collected immediately before and after LBNP procedure. LBNP produced extensive transcriptomic response at post- compared with pre-LBNP, including natural killer cell-mediated immunity activation and gas transport processes inhibition. Differentially expressed microRNAs (miRNAs) also regulated these enriched processes. Tolerance group-specific signals include alpha-beta T cell activation and major histocompatibility complex (MHC) class II protein complex assembly inhibition in HT group. Integrated analysis of multiple molecular layers demonstrated a role of cytokines and epigenetic regulators in molecular mechanisms of compensating for progressive hemorrhage. Overall, our results indicate that individual tolerances to central hypovolemia are associated with specific genomic mechanisms underlying the capacity to compensate for severe blood loss.<b>NEW & NOTEWORTHY</b> This study investigated the first multiomics data for association with tolerance to central hypovolemia in humans. Analyzing gene expression, proteins, and genetic variants in individuals with high and low tolerance to simulated hemorrhage, the findings show that severe blood loss causes widespread transcriptional changes, including the activation of innate immune system pathways and inhibition of gas transport processes. This research can help identify molecular factors that influence individuals' tolerance levels for progressive blood loss.</p>","PeriodicalId":20129,"journal":{"name":"Physiological genomics","volume":" ","pages":"102-114"},"PeriodicalIF":2.5,"publicationDate":"2026-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145912799","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Rodents exposed to placental ischemia in utero display sex differences in brain miRNA expression, mitochondrial function, and blood pressure in adulthood.","authors":"Savanna Leigh Smith, Angie Castillo, Jonna Smith, Kylie Jones, Kumudu Subasinghe, Robert Barber, Nicole R Phillips, Ahfiya Howard, Allison Burkes, Harlan Jones, Mark W Cunningham","doi":"10.1152/physiolgenomics.00086.2025","DOIUrl":"10.1152/physiolgenomics.00086.2025","url":null,"abstract":"<p><p>Placental ischemia (PI), a prenatal stressor, affects ∼1 in 10 human pregnancies worldwide and is associated with several pregnancy complications such as preeclampsia, placental abruption, and intrauterine growth restriction (IUGR). Both human and animal IUGR fetuses have an increased risk of developing hypertension (HTN) in adulthood, with males having a higher risk. Furthermore, multiple studies suggest that changes in brain function and molecular markers may contribute to HTN development. However, the alterations in brain mitochondrial dysfunction (MtDys), oxidative stress (OS), and epigenetic changes (miRNAs) in forebrain and midbrain collectively have not been investigated. Thus, we hypothesize that the sex difference in high blood pressure (HBP) is due to changes in miRNAs, brain MtDys, and increased OS in IUGR males (M) but not IUGR females (F). To test this hypothesis, IUGR and control (CON) M and F Sprague Dawley rats were evaluated at 16-18 wk (adulthood). IUGR adults were generated from PI dams, and CON adults from normal pregnant dams. Results identified 11 differentially expressed miRNAs in IUGR versus CON, with let-7d-3p miRNA being upregulated in IUGR M. IUGR M also displayed HBP, MtDys [decreased adenosine triphosphate (ATP)], and OS (∼50% increase in hydrogen peroxide). Conversely, mitochondrial G protein elongation factor (GFM-1), a protein regulated by let-7d-3p, and electron transport chain (ETC) proteins were increased with no changes in ATP production in IUGR F. In summary, our data suggest that increases in let-7d-3p will inhibit the compensatory increase in GFM-1 and ETC proteins needed to prevent HBP and cerebral OS in IUGR M. However, unchanged let-7d-3p may increase GFM-1 and ETC proteins in IUGR F to inhibit brain MtDys, OS, and HBP. Findings from this study provide insights into the mechanisms linking epigenetic changes to brain MtDys and OS along with HTN in adults born IUGR.<b>NEW & NOTEWORTHY</b> Adult IUGR male rodent offspring exposed to placental ischemia in utero have elevated mean arterial blood pressure with increased brain miRNA let-7d-3p expression, mitochondrial dysfunction, and oxidative stress, while adult IUGR females do not. Moreover, our results suggest that brain epigenetic changes may contribute to mitochondrial dysfunction and oxidative stress, eventually leading to hypertension. In conclusion, lifetime health begins in utero, and patients and healthcare providers should be aware of the consequences that prenatal stressors have on long-term health.</p>","PeriodicalId":20129,"journal":{"name":"Physiological genomics","volume":" ","pages":"73-88"},"PeriodicalIF":2.5,"publicationDate":"2026-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145775225","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}