Physiological Reports最新文献

Pilocarpine-induced sweat testing offers a laboratory-based method for assessing sweat composition, but its comparability to exercise sweating remains unclear. Establishing a relationship between this resting test and exercise sweating is important for practitioners when in-exercise sampling is impractical. This study compared sweat sodium concentration ([Na⁺]) between pilocarpine- and exercise-induced sweat across exercise intensities. 15 well-trained athletes (10 male, 5 female) performed 3 × 20 min cycling bouts (low [LO], moderate [MOD], and high [HI] intensity) and 4 pilocarpine sweat tests. Sweat was collected from the forearm using pilocarpine iontophoresis at rest, and a macroduct collector during exercise. Exercise [Na⁺] increased with intensity (LO = 44.5 ± 15.6, MOD = 54.9 ± 16.9, HI = 61.3 ± 21.3 mmol·L^-1; p < 0.001) alongside sweat rate (LO = 0.62 ± 0.2, MOD = 1.26 ± 0.3, HI = 1.92 ± 0.6 L·h^-1). Pilocarpine [Na⁺] overestimated exercise [Na⁺] at LO, matched at MOD, and underestimated at HI. Pilocarpine [Na+] was stable across four visits (p = 0.263, coefficient of variation 5.5%). In trained athletes, pilocarpine testing shows intensity-dependent agreement with exercise [Na⁺]: closest at moderate workloads, with predictable bias at the extremes. Under standardized conditions, it provides a practical alternative for hydration planning when exercise testing is not feasible.

Cardiovascular autonomic modulation (CAM) and cardiorespiratory fitness (CRF) are well-established predictors of health. Identifying metabolites associated with integrated CAM-CRF profiles may help characterize healthy physiological states. This study aimed to investigate metabolic signatures representing distinct CAM-CRF profiles in apparently healthy individuals. Non-obese individuals (n = 127, 43 ± 14 years) underwent fasting blood collection for serum metabolome (SM) analysis, cardiovascular assessment, and a cardiopulmonary exercise test to access CAM and CRF. CAM-CRF profiles were obtained separately by sex using principal components analysis (PCA) of CAM and CRF. Subjects' scores from the first two principal components of the PCA were used to generate the groups. Groups' SM were compared using one-way ANOVA (controlling for age) and metabolite correlations were analyzed using the subjects' scores (controlling for age and body mass index), considering p < 0.01. In females, low sebacic acid levels were associated with high cardiac parasympathetic modulation (CPM) and greater cardiovascular complexity. In males, low ornithine levels corresponded to a profile with high CPM, baroreflex sensitivity (BRS), and CRF. Choline, betaine, N,N-dimethylglycine levels in females, and glucose and sarcosine in males, were negatively correlated with CPM, BRS, CRF and cardiovascular complexity. These metabolites reflect integrated CAM-CRF conditions, enhancing the understanding of underlying metabolic profiles.

Metabolic dysfunction-associated steatotic liver disease (MASLD) is a growing public health concern characterized by hepatic triglyceride (TG) accumulation, inflammation, and fibrosis. Renalase is known for its role in blood pressure regulation and catecholamine metabolism, but recent evidence suggests broader cytokine-like functions. Moreover, its involvement in MASLD remains unclear. In this study, we examined the effects of renalase deficiency on hepatic lipid metabolism in a Gubra Amylin NASH (GAN) diet-induced MASLD model using renalase knockout (KO) mice. Our results show that renalase KO mice exhibited reduced hepatic TG levels, accompanied by decreased gene and protein expression of Srebf1 involved in lipid synthesis, and lower gene expressions of antioxidant and fibrosis markers in KO-GAN compared with wild type (WT)-GAN. Additionally, in vitro experiments using AML12 cells with renalase knockdown confirmed reduced intracellular TG accumulation and lipid synthesis gene expression. Notably, the phosphorylation of Akt was significantly reduced in the liver of renalase-KO mice, indicating that Akt signaling plays a critical role in the observed decrease in hepatic TG levels. These findings suggest that renalase regulates hepatic lipid metabolism through the Akt-Srebf1 pathway, and its deficiency attenuates TG accumulation, suggesting that renalase may modulate early hepatic lipid deposition that progresses toward MASLD.

Chloride intracellular channels (CLICs) are important in cardiac cellular physiology. We aimed to determine the pathophysiological roles of CLICs in the heart. For this, we analyzed CLIC expression in cardiomyocytes in a mouse transverse aortic constriction (TAC) model to induce cardiac hypertrophy and failure, as well as in ventricular myocytes from patients with dilated cardiomyopathy (DCM) using single-cell RNA-sequencing. Single-ventricular myocytes were isolated from the left ventricular free wall of C57BL/6J mice after TAC (pre-TAC; Day 3 post-TAC; and Weeks 1, 2, 4, and 8 post-TAC). Gene expression was compared with data from sham controls. In mice, CLIC1 and CLIC4 expression significantly increased in Day 3 and Weeks 1, 2, and 4 post-TAC. CLIC5 expression showed an increase during all phases. Kyoto Encyclopedia of Genes and Genomes pathway analysis for genes associated with CLIC1, CLIC4, and CLIC5 revealed a strong association between focal adhesion activation and actin cytoskeleton regulation pathways linked to extracellular matrix (ECM) remodeling. CLIC1 and CLIC4 expression was also higher in cells from patients with DCM. Single-cell RNA-sequencing revealed the possible role of CLICs in myocardial ventricular remodeling linked to ECM, proposing their potential as therapeutic targets for cardiac hypertrophy and failure.

Sex differences in the metabolic and anti-inflammatory effects of exercise have been reported, but whether males and females exhibit a differential response to exercise in a setting of cardiometabolic disease is unknown. The objective of this study was to investigate the glucose handling, adipose and cardiac effects of voluntary exercise in male and female mice in a cardiometabolic disease setting induced by a high-fat diet (HFD). The extent of exercise tolerance improvement was similar between HFD male and HFD female mice with running wheel access, despite greater daily running distances in female HFD mice. Exercise attenuated HFD-induced increased body and fat mass in females but had no effect in males. A slight improvement in insulin tolerance was observed in HFD males only. The anti-inflammatory effects of exercise were evident in both HFD males and HFD females, but the inflammatory cell types and tissue depots involved were sex-specific. Cardiac diastolic function was improved with exercise in HFD females but not HFD males. Surprisingly, cardiomyocyte dimensions increased with exercise in HFD females and decreased with exercise in HFD males. This study provides the first evidence that the cardiometabolic effects of exercise are differentially elicited in males and females in a metabolic disease setting.

Cumulus cells (CCs), derived from granulosa cells, play a key role in supporting oocyte maturation and development through bidirectional communication. However, their electrophysiological properties in humans are poorly defined. Here, we characterized ionic currents and their modulation in primary human CCs obtained from patients undergoing in vitro fertilization. Whole cell patch-clamp recordings identified three electrophysiological sub-populations: CC-type 1, expressing voltage-dependent K⁺ currents supported mainly by potassium voltage-gated channel subfamily A member 5 (K_V1.5, KCNA5); CC-type 2, predominantly showing a barium-sensitive cationic current attributable to transient receptor potential cation channel subfamily M member 5 (TRPM5); and CC-type 3, displaying mainly a noisy and voltage-dependent K⁺ current typical of potassium calcium-activated channel subfamily M alpha 1 (BK_Ca, KCNMA1). Pharmacological experiments, immunocytochemistry and rt-PCR confirmed the molecular expression of KCNA5, TRPM5 and KCNMA1. Mild extracellular acidification (pH = 6.2) rapidly and reversibly blocked TRPM5-like current, both inward and outward. Furthermore, 100 μM ATP induced metabotropic responses, evoking coupled intracellular Ca²⁺ release and activating TRPM5-mediated currents, as demonstrated by experiments with patch-clamp and FURA-2 calcium imaging. These findings reveal that human CCs integrate extracellular acidity and purinergic signals via distinct ion channels, suggesting a role as electrochemical sensors of the follicular microenvironment.

The purpose of this cross-sectional study was to determine the effect of at-risk drinking on central hemodynamics and aortic stiffness in midlife adults. A total of 38 midlife men and 41 postmenopausal women, aged 50-64 and free of major clinical diseases, were included. Based on USAUDIT-C scores derived from the U.S. Alcohol Use Disorder Identification Test, participants were classified as low-risk drinkers (n = 50) or at-risk drinkers (n = 29). Central blood pressure (BP), aortic wave reflection indices, as well as carotid-to-femoral pulse wave velocity (cfPWV; a measure of aortic stiffness) were measured. Regardless of sex (p = 0.11 for both), among participants free of antihypertensive medications (n = 51), at-risk drinkers had higher central systolic (p = 0.002) and diastolic BP (p < 0.001) compared with low-risk drinkers, while there was no between-group difference in central BP among treated participants (n = 28; p ≥ 0.41). Among untreated participants, higher USAUDIT-C scores remained independently associated with elevated systolic (p < 0.001) and diastolic BP (p = 0.003), after controlling for wave reflection indices and cfPWV. Regardless of antihypertensive medication use (p ≥ 0.25) and sex (p ≥ 0.10), no between-group differences were observed in aortic wave reflection indices (p ≥ 0.18) and cfPWV (p = 0.16). These findings suggest that elevated central BP associated with at-risk drinking is related to mechanisms other than enhanced aortic wave reflection or aortic stiffening.

Cardiovascular disease is exacerbated by diabetes through hyperglycemia-induced endothelial dysfunction, which arises from oxidative stress. Glutamine is postulated to decrease oxidative stress; however, its effect on endothelial dysfunction in hyperglycemia is unknown. Therefore, we investigated how glutamine affects endothelial function in normal and high glucose. Human coronary artery endothelial cells were treated with 0, 0.5, or 2 mM glutamine in 5.5 or 15 mM glucose for 24 h. We then assessed cell proliferation, oxidative stress, cell survival, and endothelial nitric oxide synthase (eNOS) activity. Our data showed that independent of glucose concentration, glutamine increased proliferation by up to 3.5-fold. Furthermore, glutamine metabolism through glutaminase-1 reduced oxidative stress and cell death by up to 70% and 94%, respectively, by doubling glutathione and NADPH. Glutamine also increased ex vivo vasodilation in isolated murine carotid arteries without altering eNOS activity or nitric oxide in vitro, suggesting that the enhanced vasodilation results from reduced oxidative stress. These findings indicate that glutamine mitigates endothelial cell oxidative stress by enhancing reducing capacity, which may protect against diabetic cardiovascular disease.

Intraflagellar transport protein 88 (IFT88) is essential for primary and motile cilia formation. In murine models and humans, Ift88 mutations contribute to renal cysts, epithelial proliferation and impaired immune responses. In mice, Ift88 knockout (KO) reduces airway cilia, increases airway epithelial proliferation and hyperreactivity, elevates IL-22 and decreases lung T regulatory cells. Pulmonary hypertension (PH) is a deadly disease marked by aberrant metabolism and immunoinflammatory mediators causing vasoconstriction and vascular remodeling. Endothelial-to-mesenchymal transition (EndMT) contributes to PH, and endothelial-specific Ift88 KO promotes endothelial proliferation and EndMT. We hypothesized that global loss of Ift88 causes PH. We assessed PH indices at 2 and 14 weeks postdeletion in tamoxifen-inducible Ift88 KO mice. These mice showed signs of PH, including increased right ventricular systolic pressure, cell proliferation in the walls of resistance arteries, and arterial wall thickening. At the early time point examined, we did not detect evidence of lung inflammation or EndMT. Because this is a tamoxifen-induced global Ift88 KO model, we cannot attribute the PH features to gene deletion in specific vascular cells, nor can we rule out the possibility that tamoxifen administration, global Ift88 deletion, the associated weight gain and food restriction may have influenced cardiovascular physiology in these mice.

Physical performance can be improved in aerobic athletes and breath-hold divers (BHD) by limb exposure to repetitive ischemia: remote ischemic conditioning (RIC). RIC protects against cardiac ischemia, and its blood-borne transferable substrate could be lactate. Accordingly, lactate added to whale blood increases oxygen unloading and adult seals possess higher cardiac lactate dehydrogenase activity (LDHa) than terrestrial mammals. Because BHD and adult diving mammals share adaptations to hypoxia, including lactate metabolization during apnea, we hypothesized that BHD compared to BMI/VO₂max-matched aerobic controls have higher LDHa and lactate added to blood from BHD unloads oxygen more efficiently. Six BHD and six matched aerobic controls underwent RIC: three cycles of 5-min inflation and 4-min deflation of a blood pressure cuff on the dominant arm, maximum apnea after three submaximal apneas (BHD only), and a VO₂max-test. Blood-samples were collected from the nondominant radial artery and the vena basilica of the dominant arm at rest, before termination of the three interventions, and for LDHa. Blood gases were compared to samples added lactate or placebo suspension. BHD had ⁓30% higher cardiac/erythrocyte LDHa compared to controls (p < 0.05). Lactate added to arterial blood from BHD after RIC increased oxygen unloading (p < 0.05). PaO₂ decreased ⁓66% during apnea (375+/-49 s; p < 0.001; BHD only). We conclude that 1 (erythrocyte- and cardiac-LDHa is higher in BHD compared to matched controls, and 2) lactate facilitates oxygen-unloading in blood from BHD after RIC, similar to diving mammals.