Physiological Reports最新文献

The prevalence and incidence of Crohn's disease (CD) in pediatric populations have been steadily increasing. Growing evidence suggests that gut microbiomal community differences play a critical role in the pathogenesis of CD. Additionally, the clinical course of patients with CD is unpredictable, making treatment decisions challenging. We investigated the fecal microbiome of newly diagnosed, treatment-naïve pediatric CD patients (n = 43) compared to age- and sex-matched controls with other functional gastrointestinal disorders (n = 139). We also correlated microbial changes with CD disease activity, measured by the Pediatric Crohn's Disease Activity Index (PCDAI). Our results showed that microbial richness and diversity were significantly lower in CD patients. Furthermore, taxonomic analysis revealed an enrichment in pro-inflammatory bacteria (Fusobacteria and Proteobacteria) and depletion in favorable bacteria (Firmicutes and Verrucomicrobia). Higher PCDAI scores were linked to the enrichment of genera harboring pro-inflammatory taxa (Hungatella and Veillonella) and decreased abundance of genera harboring protective taxa (Lachnospiraceae). Our study underscores the potential of fecal microbiome profiling as an effective tool for understanding CD pathogenesis, identifying microbial biomarkers, and predicting disease activity for treatment response. This, in turn, can help to improve personalized treatment and management strategies in pediatric CD.

Cardiac fibrosis represents a consequence of hypertensive heart disease and is associated with ventricular dysfunction, arrhythmias, and mortality. Arginine vasopressin (AVP) promotes myofibroblast proliferation and collagen synthesis through V1a receptors. While hepatic studies suggest that AVP deficiency attenuates fibrosis, its cardiac impact remains unclear. This study evaluated the effects of AVP deficiency induced by neurointermediate pituitary lobectomy (NIL) and pharmacological V1a/V2 blockade with conivaptan (CV) in rats with fibrosis from abdominal aortic stenosis (AAC). Wistar rats were divided into seven groups with 10 animals each. Clinical variables and histopathology (H&E, Masson's trichrome, picrosirius red) were assessed. ANOVA, Fisher and Mantel-Cox tests were applied. The Fibrosis (F) group developed hypertrophy, hypertension, higher arrhythmia risk and increased fibrosis. In contrast, F+NIL and F+CV showed blood pressure and cardiac morphology comparable to controls, reduced arrhythmia risk and significantly less fibrosis. Histologically, F+NIL achieved partial regression, whereas F+CV nearly normalized tissue architecture. In conclusion, AVP deficiency or receptor blockade decreases and reverses AAC-induced fibrosis, improving hemodynamic, electrical, and structural outcomes. V1a/V2 blockade emerges as a potential therapeutic strategy.

Mathematical models are essential for understanding oxygen transport and utilization during metabolic transitions. An electrical analogy concept proposed that exponential PO₂ transients arise from interaction between oxygen storage capacitance and transport conductances, but lacked explicit circuit representation limiting quantitative predictions and experimental testing. We developed an explicit electrical circuit model with discrete resistive and capacitive components in physiologically defined topology to generate testable predictions for interstitial PO₂ transition dynamics during rest-work transitions in skeletal muscle. Circuit topology was constructed based on established physiological relationships in rat spinotrapezius muscle. The model equated oxygen partial pressure to voltage, oxygen flux to current, delivery and metabolic barriers to resistances, and tissue oxygen storage to capacitance. The model predicted that transition time constants should equal the product of capacitance and equivalent circuit resistance. Predictions were validated using interstitial PO₂ measurements during rest-work-rest transitions. The model successfully predicted asymmetric transition kinetics, with time constant ratios matching steady-state PO₂ ratios. Application to young (3-month) and old (23-month) rats quantified age-related changes: 2.5-fold higher delivery resistance in old muscle with compensatory 5.4-fold metabolic resistance reduction during exercise versus 3.1-fold in young muscle. An explicit, validated electrical circuit model confirmed that PO₂ transition kinetics are governed by capacitance-resistance interactions and quantitatively separated delivery versus metabolic limitations in aging muscle.

Siberian huskies (SH) and Alaskan huskies (AH), sharing ancestry with ancient sled dogs, were hypothesized to achieve similar skeletal muscle (SM) mitochondrial respiration capacities and densities through endurance training. High-resolution respirometry of SM biopsies from SH and AH during off-season (5 SH, 4 AH) and racing-season (5 SH, 7 AH) revealed a striking increase in mass-specific succinate-linked mitochondrial complex II (CII) activity during racing-season, in both SH (+75%) and AH (+129%). These increases were accompanied by increased protein content in SM for both SH (+37%) and AH (+56%). Elevated CII respiratory capacity can potentially reflect increased fatty acid utilization. NADH-linked complex I (CI) respiration increased significantly only in AH (+35%), which also, unlike SH, exhibited significantly elevated citrate synthase activity (+270%). Both groups showed reduced protein-specific residual oxygen consumption during racing-season (SH: -45%, AH: -48%) and increased reactive oxygen species production. Together, these changes point to more efficient mitochondria with minimized energy loss in raced dogs. A minimally invasive sampling approach was validated, using NSAIDs, local anesthesia, light oral sedation, a micro biopsy gun, and individualized environments to minimize distress. This secured good animal welfare and provided a practical method for field-based or repeated SM biopsies without general anesthesia.

High-altitude (HA) exposure induces cardiovascular, respiratory, and metabolic adjustments that often impair exercise performance. These physiological responses depend on hypoxic severity, exposure duration, and individual susceptibility. Although full acclimatization generally requires about 7 days, early adaptations can emerge within the first 72 h. This study aimed to characterize these early responses and to evaluate the potential of mathematical modeling to predict HA-related exercise performance decline. Nine healthy volunteers (age: 24.4 ± 3.3; weight: 63.7 ± 11.8; height: 169.4 ± 8.4; female: 44%) completed maximal cardiopulmonary exercise tests under three conditions: at sea level (SL), and at 3015 m after 12 h (HA12h) and 60 h (HA60h) of exposure. Although 60 h at HA was insufficient for full acclimatization, significant differences were observed between HA12h and HA60h, indicating partial physiological adaptation. Maximal power output declined at both HA time points. Notably, HA-induced performance deterioration was accurately predicted (R² = 0.81) using SL-derived parameters, particularly maximal oxygen pulse (VO₂/HR_max) and the ventilatory equivalent for carbon dioxide (VE/VCO₂). These findings provide novel insights into early physiological responses to HA and support the development of individualized, model-based tools to anticipate performance loss and optimize training and acclimatization strategies.

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.

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.

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.