Sex-specific Responses Research Articles

Interleukin-1β signalling in muscle atrophy: linking inflammation, sex-specific responses and exercise in cancer cachexia.

Interleukin-1β signalling in muscle atrophy: linking inflammation, sex-specific responses and exercise in cancer cachexia.

The Efficacy of Nutritional Strategies and Ergogenic Aids on Acute Responses and Chronic Adaptations to Exertional-Heat Exposure: A Narrative Review

Global warming is attributed to an increased frequency of high ambient temperatures and humidity, elevating the prevalence of high-temperature-related illness and death. Evidence over recent decades highlights that tailored nutritional strategies are essential to improve performance and optimise health during acute and chronic exertional-heat exposure. Therefore, the purpose of this review is to discuss the efficacy of various nutritional strategies and ergogenic aids on responses during and following acute and chronic exertional-heat exposure. An outline is provided surrounding the application of various nutritional practices (e.g., carbohydrate loading, fluid replacement strategies) and ergogenic aids (e.g., caffeine, creatine, nitrate, tyrosine) to improve physiological, cognitive, and recovery responses to acute exertional-heat exposure. Additionally, this review will evaluate if the magnitude and time course of chronic heat adaptations can be modified with tailored supplementation practices. This review highlights that there is robust evidence for the use of certain ergogenic aids and nutritional strategies to improve performance and health outcomes during exertional-heat exposure. However, equivocal findings across studies appear dependent on factors such as exercise testing modality, duration, and intensity; outcome measures in relation to the ergogenic aid’s proposed mechanism of action; and sex-specific responses. Collectively, this review provides evidence-based recommendations and highlights areas for future research that have the potential to assist with prescribing specific nutritional strategies and ergogenic aids in populations frequently exercising in the heat. Future research is required to establish dose-, sex-, and exercise-modality-specific responses to various nutritional practices and ergogenic aid use for acute and chronic exertional-heat exposure.

The Role of Probiotics in Modulating Myocardial Infarction and Depression-like Symptoms: A Study on Sex-Specific Responses

Background/Objectives: This study explores the effects of two probiotics, Lactobacillus helveticus R0052 and Bifidobacterium longum R0175, on myocardial infarction (MI) and associated depression-like behaviours, with a focus on sex differences. Methods: MI was induced in adult male and female rats by occluding the left anterior coronary artery for 30 min, followed by 24 h of reperfusion. Probiotics were administered via drinking water for at least two weeks before ischemia. Infarct size, plasma C-reactive protein (CRP), estradiol levels, and intestinal permeability were then measured. Two weeks after, MI subgroups of rats were tested for depression-like behaviours. Results: We found a significant interaction between sex and probiotics in relation to infarct size. Probiotics significantly reduced the infarct size compared to the vehicle group in female rats but not in males. Probiotics increased the plasma estradiol levels and reduced the CRP concentrations in females, suggesting anti-inflammatory and cardioprotective properties. Probiotics significantly increased intestinal resistance following MI in males only, suggesting sex-specific physiological responses to treatment. Probiotics enhanced social interaction in males with MI but not in females. Similarly, in the forced swim test, probiotics reduced immobility in males with MI but increased it in females, further underscoring the sex-dependent effects of probiotics. Conclusions: This study reports cardioprotective effects of probiotics upon MI in female rats, while benefits in male rats were rather at the behavioural level. These results highlight distinct physiological and behavioural responses between sexes, emphasizing the need to account for sex differences in future tests of probiotics as a prophylactic treatment for MI.

Impact of maternal high-fat diet on offspring gut microbiota during short-term high-fat diet exposure in mice.

Alterations in the gut microbiome have been linked to obesity, with maternal high-fat diet (HF) playing a role in shaping offspring microbiome composition. However, the sex-specific responses to maternal HF diet and the impact of subsequent dietary challenges remain unclear. This study investigated the effects of maternal HF diet on offspring gut microbiota structure and predicted functional profile in response to short-term postnatal HF diet exposure with a focus on sex-specific responses. Female and male offspring of maternal control (C) diet or maternal HF diet were weaned onto C diet or HF diet. Offspring were euthanized at 13 weeks of age and cecal contents were collected for bacterial taxonomic profiling. Maternal HF diet reduced α-diversity, notably in male offspring weaned onto HF diet. Sex-specific differences were observed in the gut microbial composition and predicted functional potential. Furthermore, the influence of maternal diet on bacterial community structure and functional potential varied depending on postnatal diet. Maternal HF diet led to increased relative abundance of Corynebacterium in female offspring and decreased abundance of Akkermansia and Roseburia in male offspring. These findings underscore the sexually dimorphic nature of maternal HF diet effects on gut microbiota composition and function, with implications for developmental programming and metabolic health.

Isolated Rib Response and Fracture Prediction for Young Mid-Size Male, Enabled by Population Specific Material Models and Rib Cross-Sectional Geometry.

Thorax injury remains a primary contributor to mortality in car crash scenarios. Although human body models can be used to investigate thorax response to impact, isolated rib models have not been able to predict age- and sex-specific force-displacement response and fracture location simultaneously, which is a critical step towards developing human thorax models able to accurately predict injury response. Recent advancements in constitutive models and quantification of age- and sex-specific material properties, cross-sectional area, and cortical bone thickness distribution offer opportunities to improve rib computational models. In the present study, improved cortical and trabecular bone constitutive models populated with age-specific material properties, age- and sex-specific population data on rib cross-sectional area, and cortical bone thickness distribution were implemented into an isolated 6th rib from a contemporary human body model. The enhanced rib model was simulated in anterior-posterior loading for comparison to experimental age- and sex-specific (twenty-three mid-size males, age range of 22- to 57-year-old) population force-displacement response and fracture location. The improved constitutive models, populated with age-specific material properties, proved critical to predict the rib failure force and displacement, while the improved cortical bone thickness distribution and cross-sectional area improved the fracture location prediction. The enhanced young mid-size male 6th rib model was able to predict young mid-size male 6th rib experimental force-displacement response and fracture location (overpredicted the displacement at failure by 35% and underpredicted the force at failure by 8% but within ±1 SD). The results of the present study can be integrated into full body models to potentially improve thorax injury prediction capabilities.

Sex-specific immune responses to COVID-19 vaccination in end-stage renal disease patients

Abstract Background End-stage renal disease (ESRD) patients have muted memory B cell formation and reduced humoral responses to COVID-19 vaccination; however, early innate immune responses have yet to be characterized. Sex-stratification is also limited in COVID-19 vaccination research. Methods We collected blood before (BD1) and 1-4 days post-dose 1 (PD1) of BNT162b2 vaccination for RNA-sequencing in ESRD patients (n = 35 BD1; 18 PD1) and healthy controls (HC) (n = 31 BD1; 30 PD1). Additionally, 20 plasma cytokines were quantified in ESRD patients (n = 39 BD1, 35 PD1) and HC (34 BD1, 15 PD1). Results Transcriptional profiling of vaccine responses identified 125 significantly differentially expressed genes (DEG) (padj<0.04) in ESRD patients and 107 DEGs (padj<0.05) in HC. 71 DEGs were shared, 54 unique to ESRD, and 36 unique to HC. DEG, pathway analyses, and cytokine responses in the combined dataset showed ESRD patients were more inflamed than HC at baseline, with an elevated inflammatory cytokine profile compared to HC. These results were driven by female ESRD patients where IL-2, IL-10, and IP-10 were more significant in females (p < 0.001) compared to males (p < 0.01). While IL-6, IFN-γ, IL-13, eotaxin, were exclusively associated in females (p < 0.05). Healthy females also had a stronger immunological response to vaccination compared to healthy males. Conclusions Despite baseline inflammation, ESRD patients were able to mount similar early immune responses to vaccination as HC, with females in both populations more reactogenic than males. Sex-stratification is recommended for ongoing immunological research to better understand unique responses to COVID-19 vaccination. Key messages • End-stage renal disease patients have similar early innate immune responses to COVID-19 vaccination as healthy controls. • Sex-stratification is important to identify unique immunological responses that may be leveraged for sex-specific vaccination strategies.

Influence of peak exercise-induced blood pressure on basal to apical myocardial wall thickness in elite athletes: a sex-specific CMR study

Abstract Background Understanding the sex-specific physiological remodelling response of the myocardial walls to peak exercise-induced blood pressure (SBPpeak) is essential for distinguishing healthy adaptation from pathological remodelling in athletes. Purpose We investigated how SBPpeak relates to myocardial wall thickness measured using cardiac magnetic resonance imaging (CMR) in elite athletes. Methods Cross-sectional analysis of healthy elite athletes included in the ELITE study who underwent both cardiopulmonary exercise testing (CPET) and CMR. Imaging software’s built-in AI option determined average end-diastolic wall thicknesses of all sixteen AHA-defined segments on short-axis cine images with four-chamber long-axis reference. Our primary metrics of interest were Spearman's correlations between SBPpeak and left ventricular mass indexed to body surface area (LVM/BSA), as well as average wall thickness across the sixteen myocardial segments, stratified by sex and endurance/non-endurance sports status. Secondary analyses involved regression models to evaluate the influence of SBPpeak on myocardial wall thickness, adjusting for sex, body size, CPET variables and sport type. Results In 75 athletes (median age: 24; 71% female; 61% engaged in endurance sports), CPET and CMR were performed within a median interval of 5 months [interquartile range: 1-13 months]. SBPpeak was similar in female and male athletes (170 [160-180] vs. 174 [169-184] mmHg, p=0.121, respectively) and in endurance and non-endurance athletes (both 170 [160-180] mmHg, p=0.625). Female elite athletes showed weak to moderate positive correlations between SBPpeak and the majority of basal and mid-ventricular AHA segments (rho = 0.27 – 0.48, Figure). This was most pronounced in the mid-ventricular anterolateral segment (AHA06: rho = 0.48, p<0.001). LVM/BSA in females was positively correlated with SBPpeak (rho = 0.31, p=0.025). Male elite athletes demonstrated greater absolute wall thickness across all AHA segments compared to females, however, there was a moderate correlation with SBPpeak exclusive to the basal anterior segment (AHA01: rho = 0.48, p=0.028). Backward stepwise multivariate regression analyses (Table) revealed SBPpeak as an independent predictor of the thickness of all basal AHA segments except for the basal inferoseptal segment (AHA03), and the mid-anterior and anterolateral segments. Associationswere maintained after adjustment for maximum wattage, body surface area, and sex, with type of sports consistently excluded from the models. Conclusion In the extreme phenotypes of elite athletes, SBPpeak correlates especially with basal myocardial thickness, independent of sex, BSA and maximum work rate influences. We found stronger associations between SBPpeak and myocardial adaptation in female athletes. These findings suggest a paramount role of exercise-induced blood pressure on basal myocardial remodelling surpassing the effect of sports type.Figure:segmental polar plot (heat map)Table:GAM regression models

Sex-specific differences in the severity of pulmonary hypoplasia in experimental congenital diaphragmatic hernia and implications for extracellular vesicle-based therapy.

Amniotic fluid stem cell extracellular vesicles (AFSC-EVs) hold regenerative potential to treat hypoplastic lungs secondary to congenital diaphragmatic hernia (CDH). This study aims to investigate sex-specific differences in pulmonary hypoplasia severity and responses to AFSC-EV administration in an experimental CDH mouse model. C57BL/6J dams were fed with nitrofen + bisdiamine (left-sided CDH) or olive oil only (control) at embryonic day (E) 8.5. Lungs were dissected (E18.5), grown ex vivo and treated with medium ± AFSC-EVs that were collected via ultracentrifugation and characterized (nanoparticle tracking analysis, electron microscopy, Western blotting). Pulmonary hypoplasia was assessed via mean linear intercept (MLI). Gene and protein expression changes (Cd31, Enos, Il1b, TNFa) were measured via RT-qPCR and immunofluorescence. Pups were genotyped for Sry. Experimental CDH showed a male predominance without sex differences for pulmonary hypoplasia severity, fetal lung vascularization, and inflammation. AFSC-EV administration led to improved lung growth (decreased MLI), improved fetal lung vascularization (increased Cd31 and Enos), and decreased fetal lung inflammation (Il1b, TNFa). There was no sex-specific response to AFSC-EV administration. This study shows sex-independent impaired lung growth, vascularization and fetal lung inflammation in a CDH mouse model. Antenatal administration of AFSC-EVs reverses aspects of pulmonary hypoplasia secondary to CDH independent of the biological sex.

Sex differences in management of LDL-cholesterol in patients with chronic coronary syndrome

Abstract Background Effective management of low-density lipoprotein cholesterol (LDL-C) is crucial for preventing recurrent cardiovascular (CV) events in patients with chronic coronary syndrome (CCS). Sex may impact the LDL-C management, by gender bias and/or sex-specific responses to pharmacological interventions. Purpose We examined sex-specific LDL-C management in CCS patients, assessing target achievement rates and their implications for CV outcomes. Methods In the international CLARIFY registry, we included 22,134 CCS patients with baseline LDL-C measurements. LDL-C levels were monitored annually over the 5-year follow-up period. Target LDL-C was set at 100 mg/dL, in line with prevailing recommendations at that time. Sex-specific differences in LDL-C were adjusted for age, geographical region and indication for lipid lowering drugs (stroke, MI, PAD). The primary endpoint was the incidence of MACE, defined as CV death or MI during the 5-year follow-up, evaluated using multivariable analysis adjusted for known predictors of recurrent CV events in CCS patients. Results Of 22,134 patients, 21.6% were women. Upon inclusion (6.5 ± 6.3 years after CCS diagnosis), women were more likely than men to have LDL-C levels above the recommended threshold (45.6% vs. 37.4%; aOR 1.47, 95%CI 1.38-1.58, p<0.001) and less likely to receive statin treatment (82.7% vs. 85.4%, p<0.001). Although women and men had comparable numbers of LDL-C measurements during follow-up, the discrepancies endured over the 5-year observation period, with women consistently showing lower likelihoods of achieving LDL-C targets at 1, 2, 3, 4, and 5 years post-inclusion (p<0.001 for all time points). Overall, women were less likely than men to have all available LDL-C concentrations within the target range (37.8% vs. 44.6%; aOR 0.70, 95% CI 0.64-0.76, p<0.001) and more likely to never reach the target LDL-C goal during follow-up (22.6% vs. 17.5%; aOR 1.43, 95% CI 1.32-1.55, p<0.001). Failing to achieve at least one LDL-C concentration below 100 mg/dL was associated with an increased risk of subsequent MACE (adjusted HR 1.57, 95%CI 1.38-1.77, p<0.001), with similar associations observed in both men (aHR 1.66, 95% CI 1.44-1.91, p<0.001) and women (aHR 1.31, 95% CI 1.01-1.70, p=0.05). Conclusion In patients with CCS, women consistently showed lower likelihood of reaching LDL-C targets throughout follow-up compared to men, even after adjusting for age, geographical region and other statin indications. Notably, women were more likely to have no LDL-C concentration within recommended range during follow-up, which is particularly concerning given its association with an increased risk of CV events. A contributing factor to this sex disparity in LDL-C control is women's lower likelihood of receiving lipid-lowering drugs than men. These results highlight the need for tailored interventions to address sex-related disparities in LDL-C management and improve cardiovascular outcomes in CCS patients.

Weight loss, changes in body composition and inflammatory status after a very low-energy ketogenic therapy (VLEKT): does gender matter?

BackgroundConsidering differences in body composition and inflammatory status between sexes, as well as recent recommendations advocating for personalized dietary approaches, this study aimed to explore how sex influences weight loss, changes in body composition, and inflammatory status in subjects with grade I and II obesity undergoing a 45-day of the Very Low-Energy Ketogenic Therapy (VLEKT).MethodsParticipants (21 premenopausal females and 21 males), included in the study adhered to the 45-day of the VLEKT and underwent assessments of anthropometric parameters (weight, height, body mass index—BMI –, and waist circumference), body composition via bioelectrical impedance analysis, and inflammatory status measured by high sensitivity C-reactive protein (hs-CRP) levels at baseline and post-intervention.ResultsAt baseline, premenopausal females and males did not differ in BMI (p = 0.100) and hs-CRP levels (p = 0.948). Males demonstrated overall larger benefits than premenopausal females from the VLEKT in terms of weight loss (Δ% = − 11.63 ± 1.76 vs − 8.95 ± 1.65 kg, p < 0.001), fat mass (Δ% = − 30.84 ± 12.00 vs -21.36 ± 4.65 kg, p = 0.002), and hs-CRP levels (Δ% = − 41.42 ± 21.35 vs − 22.38 ± 17.30 mg/L, p = 0.003). Of interest, in males phase angle values are statistically improved compared to female (Δ% = 17.11 ± 9.00 vs 7.05 ± 3.30°, p < 0.001).ConclusionThese findings underscore the importance of considering sex-specific responses in personalized obesity treatment strategies, particularly dietary interventions like VLEKTs.Graphical

Sportomics Analyses of the Exercise-Induced Impact on Amino Acid Metabolism and Acute-Phase Protein Kinetics in Female Olympic Athletes

Background: Exercise can be used as a model to understand immunometabolism. Biological data on elite athletes are limited, especially for female athletes, including relevant data on acute-phase proteins and amino acid metabolism. Methods: We analyzed acute-phase proteins and amino acids collected at South American, Pan-American, and Olympic Games for 16 Olympic sports. We compared female and male elite athletes (447 vs. 990 samples) across four states (fasting, pre-exercise, post-exercise, and resting) to understand sex-specific immunometabolic responses in elite athletes. Results: Considering all states and sports, we found that elite female athletes exhibited higher concentrations of C-reactive protein, lipopolysaccharide-binding protein, myeloperoxidase, haptoglobin, and IGF1, with ratios ranging from 1.2 to 2.0 (p &lt; 0.001). Women exhibited lower concentrations of most amino acids, except for glutamate and alanine. Although almost 30% lower in women, branched-chain amino acids (BCAAs) showed a similar pattern in all states (ρ ≥ 0.9; p &lt; 0.001), while aromatic amino acids (AAAs) showed higher consumption during exercise in women. Conclusion: We established sex dimorphism in elite athletes’ metabolic and inflammatory responses during training and competition. Our data suggest that female athletes present a lower amino acid response towards central fatigue development than male athletes. Understanding these differences can lead to insights into sex-related immuno-metabolic responses in sports or other inflammatory conditions.

Sex-Based Effects of Branched-Chain Amino Acids on Strength Training Performance and Body Composition.

Branched-chain amino acids (BCAAs) are widely studied for their effects on muscle recovery and performance. This study examined the effects of BCAA supplementation on anthropometric data, physical performance, delayed onset muscle soreness (DOMS), and fatigue in recreational weightlifters. The trial involved 100 participants (50 men and 50 women), randomized into BCAA and placebo groups. Subjects in the BCAA group took five daily capsules of 500 mg L-leucine, 250 mg L-isoleucine, and 250 mg L-valine for six months. A two-way ANOVA was used to analyze the main and interaction effects of sex and treatment. Notable findings include significant improvements in muscle recovery, as indicated by reduced DOMS, particularly in women who showed a decrement of 18.1 ± 9.4 mm compared to 0.8 ± 1.2 mm in the placebo group of a horizontal 100 mm line. Fatigue perception was also significantly lower in the BCAA group, with women reporting a greater decrease (2.6 ± 1.5 scores) compared to the placebo group (0.6 ± 0.7 scores). Strength gains were prominent, especially in men, with a 10% increase in bench press maximum observed in the BCAA group. The interaction between sex and treatment was significant, suggesting sex-specific responses to BCAA supplementation. These results underscore the effectiveness of BCAA supplementation in enhancing muscle recovery, reducing fatigue, and improving strength. This study also highlights sex-specific responses, with women benefiting more in terms of DOMS and fatigue reduction, while men experienced greater strength gains, suggesting a need for tailored supplementation strategies.

Sirtuin 3 drives sex-specific responses to age-related changes in mouse embryonic fibroblasts

The aging process is a complex phenomenon characterised by a gradual decline in physiological functions and an increased susceptibility to age-related diseases. An important factor in aging is mitochondrial dysfunction, which leads to an accumulation of cellular damage over time. Mitochondrial Sirtuin 3 (Sirt3), an important regulator of energy metabolism, plays a central role in maintaining mitochondrial function. Loss of Sirt3 can lead to reduced energy levels and an impaired ability to repair cellular damage, a hallmark of the aging process. In this study we investigated the impact of Sirt3 loss on mitochondrial function, metabolic responses and cellular aging processes in male and female mouse embryonic fibroblasts (MEF) exposed to etoposide-induced DNA damage, which is commonly associated with cellular dysfunction and senescence. We found that Sirt3 contributes to the sex-specific metabolic response to etoposide treatment. While male MEF exhibited minimal damage suggesting potential prior adaptation to stress due to Sirt3 loss, female MEF lacking Sirt3 experienced higher vulnerability to genotoxic stress, implying a pivotal role of Sirt3 in their resistance to such challenges. These findings offer potential insights into therapeutic strategies targeting Sirt3- and sex-specific signalling pathways in diseases associated with DNA damage that play a critical role in the aging process.

Sex and organ specific proteomic responses to vitamin C deficiency in the brain, heart, liver, and spleen of Gulo-/- mice.

Recent advances in mass spectrometry have indicated that the water-soluble antioxidant vitamin C differentially modulates the abundance of various proteins in the hepatic tissue of female and male mice. In this study, we performed LC-MS/MS to identify and quantify proteins that correlate with serum vitamin C concentrations in the whole brain, heart, liver, and spleen tissues in mice deficient for the enzyme L-Gulonolactone oxidase required for vitamin C synthesis in mammals. This work shows for the first time that various biological processes affected by a vitamin C deficiency are not only sex specific dependent but also tissue specific dependent even though many proteins have been identified and quantified in more than three organs. For example, the abundance of several complex III subunits of the mitochondrial electron transport chain correlated positively with the levels of serum vitamin C only in the liver and not in the other tissues examined in this study even though such proteins were identified in all the organs analyzed. Western blot analyses on the Uqcrc1 and Uqcrfs1 complex III subunits validated the mass spectrometry results. Interestingly, the ferritin subunits represented the few quantified protein complexes that correlated positively with serum vitamin C in all the organs examined. Concomitantly, serum ferritin light chain 1 was inversely correlated with vitamin C levels in the serum. Thus, our study provides an initial comprehensive atlas of proteins significantly correlating with vitamin C in four organs in mice that will be a useful resource to the scientific community.

Phlebotomy-induced anemia reduces oxygen-induced retinopathy severity and dampens retinal developmental transcriptomic pathways in rats.

Phlebotomy-induced-anemia (PIA), which induces tissue hypoxia and angiogenesis, occurs universally among infants at risk for severe retinopathy of prematurity (ROP). We hypothesized that PIA exacerbates pathologic retinal neovascularization in ROP. We induced PIA to a hematocrit of 18% among rats undergoing the established 50/10 oxygen-induced retinopathy (OIR) model. Rats were euthanized at P15 and P20, during the avascular and neovascular phases of OIR, respectively. Retinal vascular morphometry, cytokine/chemokine concentrations, transcriptomes, and mRNA expression of angiogenic and iron-deficiency markers were compared to non-PIA controls. In OIR, PIA decreased percent avascular area at P15 by 35%, percent neovascular area at P20 by 42%, and select pro-inflammatory cytokine/chemokine concentrations at both time points. At P20, PIA increased mRNA expression of angiopoietin 2/ vascular endothelial growth factor-A 2-fold and transferrin and transferrin receptor 5-fold. RNA sequencing showed dampened pathways of angiogenesis, inflammation, and neural development in anemic OIR females. Contrary to our hypothesis, PIA decreased OIR severity and retinal cytokine and chemokine levels and dampened transcriptomic pathways central to retinal vascular and neural development in neonatal rats. These data suggest PIA provides a protective effect from OIR. Further investigation into the functional effect of these molecular changes is warranted. This is the first preclinical study to investigate the impact of neonatal anemia on oxygen-induced retinopathy (OIR) outcomes. This study adds to the literature that anemia decreases neovascularization, decreases cytokine and chemokine levels, and dampens angiogenic and neural transcriptomic pathways in the rat 50/10 OIR model. The study identifies a sex-specific transcriptomic response to anemia in the 50/10 OIR model, with females primarily impacted.

Sex-specific response of the human plasma lipidome to short-term cold exposure

Cold-induced lipolysis is widely studied as a potential therapeutic strategy to combat metabolic disease, but its effect on lipid homeostasis in humans remains largely unclear. Blood plasma comprises an enormous repertoire in lipids allowing insights into whole body lipid homeostasis. So far, reported results originate from studies carried out with small numbers of male participants. Here, the blood plasma's lipidome of 78 male and 93 female volunteers, who were exposed to cold below the shivering threshold for 2 h, was quantified by comprehensive lipidomics using high-resolution mass spectrometry. Short-term cold exposure increased the concentrations in 147 of 177 quantified circulating lipids and the response of the plasma's lipidome was sex-specific. In particular, the amounts of generated glycerophospholipid and sphingolipid species differed between the sexes. In women, the BMI could be related with the lipidome's response. A logistic regression model predicted with high sensitivity and specificity whether plasma samples were from male or female subjects based on the cold-induced response of phosphatidylcholine (PC), lysophosphatidylcholine (LPC), and sphingomyelin (SM) species.In summary, cold exposure promotes lipid synthesis by supplying fatty acids generated after lipolysis for all lipid classes. The plasma lipidome, i.e. PC, LPC and SM, shows a sex-specific response, indicating a different regulation of its metabolism in men and women. This supports the need for sex-specific research and avoidance of sex bias in clinical trials.

When the Going Gets Tough, the Females Get Going: Sex-Specific Physiological Responses to Simultaneous Exposure to Hypoxia and Marine Heatwave Events in a Ubiquitous Copepod.

The existence of sex-specific differences in phenotypic traits is widely recognized. Yet they are often ignored in studies looking at the impact of global changes on marine organisms, particularly within the context of combined drivers that are known to elicit complex interactions. We tested sex-specific physiological responses of the cosmopolitan and ecologically important marine copepod Acartia tonsa exposed to combined hypoxia and marine heatwave (MHW) conditions, both of which individually strongly affect marine ectotherms. Females and males were acutely exposed for 5 days to a combination of either control (18°C) or a high temperature mimicking a MHW (25°C), and normoxia (100% O2 sat.) or mild hypoxia (35% O2 sat.). Life-history traits, as well as sex-specific survival and physiological traits, were measured. Females had overall higher thermal tolerance levels and responded differently than males when exposed to the combined global change drivers investigated. Females also showed lower metabolic thermal sensitivity when compared to males. Additionally, the MHW exerted a dominant effect on the traits investigated, causing a lower survival and higher metabolic rate at 25°C. However, egg production rates appeared unaffected by hypoxia and MHW conditions. Our results showed that MHWs could strongly affect copepods' survival, that combined exposure to hypoxia and MHW exerted an interactive effect only on CTmax, and that sex-specific vulnerability to these global change drivers could have major implications for population dynamics. Our results highlight the importance of considering the differences in the responses of females and males to rapid environmental changes to improve the implementation of climate-smart conservation approaches.

S743 Sex-specific Response Patterns to Tricyclic Antidepressants in Patients With Diarrhea-Predominant Irritable Bowel Syndrome: A Propensity-Matched, Retrospective Cohort Study

S743 Sex-specific Response Patterns to Tricyclic Antidepressants in Patients With Diarrhea-Predominant Irritable Bowel Syndrome: A Propensity-Matched, Retrospective Cohort Study

Effects of chronic stress on rat heart function following regional ischemia: a sex-dependent investigation.

Chronic psychological stress is a recognized, yet understudied risk factor for heart disease, with potential sex-specific effects. We investigated whether chronic stress triggers sex-dependent cardiac dysfunction in isolated Wistar rat hearts subjected to ischemia-reperfusion injury. The experimental cohort underwent 1 h of daily restraint stress for 4 wk versus matched controls, followed by euthanasia (sodium pentobarbital) and heart excision for ex vivo perfusion. Blood analysis revealed sex-specific alterations in stress hormones and inflammatory markers. When compared with controls, chronic restraint stress (CRS) males displayed decreased plasma brain-derived neurotrophic factor (BDNF) levels (P < 0.05), whereas CRS females exhibited elevated plasma adrenocorticotropic hormone (ACTH) (P < 0.01) and reduced corticosterone (P < 0.001) alongside lower serum estradiol (P < 0.001) and estradiol/progesterone ratio (P < 0.01). Of note, CRS females showed increased serum cardiac troponin T (P < 0.05) and tumor necrosis factor-α (TNF-α) (P < 0.01) with suppressed interleukin (IL)-1α, IL-1β, IL-6, and IL-10 levels (P < 0.05) when compared with controls. Ex vivo Langendorff perfusions revealed that CRS female hearts displayed impaired postischemic functional recovery for baseline stroke volume (SV, P < 0.01), work performance (P < 0.05), aortic output (AO, P < 0.05), coronary flow (CF, P < 0.01), and overall cardiac output (CO, P < 0.01) when compared with matched controls and CRS males (P < 0.05). Our findings reveal intriguing sex-specific responses at both the systemic and functional levels in stressed hearts. Here, the dysregulation of stress hormones, proinflammatory state, and potential underlying cardiomyopathy in females following the stress protocol renders them more prone to damage following myocardial ischemia. This study emphasizes the importance of incorporating sex as a biological variable in cardiac research focusing on stress-related cardiomyopathy.NEW & NOTEWORTHY Although chronic psychological stress is a risk factor for cardiovascular diseases, the underlying mechanisms remain poorly understood. This study revealed that chronic restraint stress resulted in systemic changes (dysregulated stress hormones, proinflammatory state) and potential cardiomyopathy in females versus controls and their male counterparts. The stressed female hearts also displayed reduced functional recovery following ex vivo ischemia-reperfusion. This highlights the importance of incorporating sex as a biological variable in cardiac research.

Mitochondrial dynamics and sex-specific responses in the developing rat hippocampus: Effect of perinatal asphyxia and mesenchymal stem cell Secretome treatment

AimsPerinatal asphyxia is one of the major causes of neonatal death at birth. Survivors can progress but often suffer from long-term sequelae. We aim to determine the effects of perinatal asphyxia on mitochondrial dynamics and whether mesenchymal stem cell secretome (MSC-S) treatment can alleviate the deleterious effects. Materials and methodsAnimals were subjected to 21 min of asphyxia at the time of delivery. MSC-S or vehicle was intranasally administered 2 h post-delivery. Mitochondrial mass (D-loop, qPCR), mitochondrial dynamics proteins (Drp1, Fis1 and OPA1, Western blot), mitochondrial dynamics (TOMM20, Immunofluorescence), as well as mitochondrial membrane potential (ΔΨm) (Safranin O) were evaluated at P1 and P7 in the hippocampus. Key findingsPerinatal asphyxia increased levels of mitochondrial dynamics proteins Drp1 and S-OPA1 at P1 and Fis1 at P7. Mitochondrial density and mass were decreased at P1. Perinatal asphyxia induced sex-specific differences, with increased L-OPA1 in females at P7 and increased mitochondria circularity. In males, asphyxia-exposed animals exhibited a reduced ΔΨm at P7. MSC-S treatment normalised levels of mitochondrial dynamics proteins involved in fission. SignificanceThis study provides novel insights into the effects of perinatal asphyxia on mitochondrial dynamics in the developing brain and on the therapeutic opportunities provided by mesenchymal stem cell secretome treatment. It also highlights on the relevance of considering sex as a biological variable in perinatal brain injury and therapy development. These findings contribute to the development of targeted, personalised therapies for infants affected by perinatal asphyxia.