Journal of applied physiology最新文献

Background: Acute hypobaric hypoxia induces rapid neurovascular adjustments in the central nervous system, yet the specific spatiotemporal dynamics of these responses remain incompletely understood. The retina, with its high metabolic demand and direct accessibility, provides a unique noninvasive model to investigate neurovascular coupling dynamics under simulated high-altitude hypoxia.

Methods: Twenty-one healthy adults underwent ophthalmic evaluations at sea level, during a stepwise ascent to 4,500 m in a hypobaric chamber (simulated altitudes: 3,500 m, 4,000 m, 4,500 m), and during a subsequent recovery phase. Images were acquired 10 minutes after reaching each plateau. Optical coherence tomography angiography (OCTA) was used to quantify vessel density (VD), perfusion area (PA), and small-vessel density (SVD). Full-field electroretinogram (ERG) was recorded under dark- and light-adapted conditions. Linear mixed-effects models and correlation analyses were used to assess altitude-related changes.

Results: The Superficial Vascular Plexus (SVP) exhibited a sustained compensatory vasodilation (increased VD and PA) across all altitudes. In contrast, ERG amplitudes declined significantly at 4,500 m, revealing a functional supply-demand mismatch. Strict statistical analysis revealed a loss of linear neurovascular correlation during hypoxia, while strong correlations re-emerged during the recovery-phase. Additionally, physiological parameters did not immediately return to baseline during recovery, indicating a distinct physiological hysteresis.

Conclusions: The retina displays differential neurovascular responses during progressive hypoxia. While the superficial microvasculature mounts a sustained compensatory response, neuronal function decompensates under severe stress. These results suggest that retinal vascular dilation reaches a functional ceiling, leading to neurovascular uncoupling, and that the system exhibits a metabolic lag during recovery.

Following pulmonary embolism (PE), up to a third of patients develop persistent activity-related dyspnea without evidence of pulmonary hypertension (PH) at rest. In such individuals, dyspnea appears to be associated with relatively high inspiratory neural drive (IND, assessed via diaphragm electromyography) during exercise. Excessive IND is multi-factorial, but the effects of regional pulmonary capillary hypoperfusion and increased physiological dead space may be contributory. We aimed to determine the effect of iNO on IND, perceived dyspnea intensity and exercise endurance in patients post-PE. We undertook a randomized, double-blind, placebo-controlled crossover study where 14 symptomatic individuals post-PE completed constant work rate cycle exercise tests while breathing iNO (40 ppm) or placebo, on separate days. Detailed measurements of expired gas, respiratory neuromechanics and perceived dyspnea were acquired at rest and throughout exercise. iNO administration, compared with placebo, was associated with reduced isotime IND and breathing effort (esophageal pressure-time product of inspiratory muscles) by 9±8 and 19±35 %, respectively (both p<0.01), increased exercise endurance time by 27±12 % (p<0.001), and reduced isotime dyspnea ratings by 1±1 Borg units (p=0.011). The reduction in IND was related to reduced dyspnea (r=0.59, p<0.018), which in turn, correlated with increased exercise endurance time (r=-0.60, p<0.024). At standardized exercise times, iNO was associated with small reductions in ventilatory requirements for CO₂ and heart rate, and increased oxygen pulse, versus placebo (all p<0.05). This study demonstrated that excessive IND contributed to troublesome dyspnea and exercise intolerance in individuals post-PE and that these could be partially mitigated by selective pulmonary vasodilation.

The ability to endure psychosocial stressors is critical for mental and physical well-being. Clarifying mechanisms that differentiate high- from low-tolerant individuals may inform resilience-oriented interventions. This exploratory study aimed to predict tolerance to the socially evaluated cold pressor test (SECPT) from a multimodal set of psychological ratings and physiological markers, quantifying how psychophysiological responses account for individual differences in acute psychosocial stress tolerance. Thirty healthy adults completed a 5-min baseline followed by the SECPT. Self-reported perceptual and affective responses, electrodermal activity, and electroencephalography (EEG; sensor-level Granger connectivity computed over a frontoparietal [FPN] scalp montage) were acquired throughout; a brief semi-structured interview complemented quantitative findings. Models were evaluated with stratified 5-fold cross-validation. A Random Forest regressor with a square-root-transformed duration target explained 23.5% of the variance. Two composite features emerged as primary, directionally opposite predictors: the Stress Response Index showed a positive effect; higher perceived stress, arousal, and pain were associated with longer tolerance, whereas FPN Causal Connectivity showed a negative effect; stronger directed influence predicted shorter tolerance. The SECPT manipulation produced a perceptual profile of higher stress, pain, and arousal with lower affective valence and perceived dominance. Sympathetic activity predominated, with an early peak and a trend toward habituation. Global FPN connectivity was attenuated, most notably over parietal, central-parietal, and frontal interhemispheric circuits. Together, these results indicate that tolerance reflects an interplay between subjective reactivity and network control dynamics. The findings provide initial, mechanistically informed markers of psychosocial stress tolerance and motivate larger studies to test generalizability and temporal dynamics.

Introduction: Modifiable health behaviors such as exercise regulate adiposity in adults, but the effects of exercise during pregnancy on infant adiposity remain understudied. This report analyzed the relationship between prenatal exercise frequency, intensity, time, type and volume (FITT-V) and infant adiposity, to better guide prenatal exercise prescription.

Methods: Female participants (body mass index = 29.0 kg/m², 30.5 years of age, with gravida = 1 and parity = 0, VO₂peak = 21.9 ml/kg/min, and pregnant for 39.6 weeks) were randomized to supervised exercise (aerobic, resistance, combination) or attention-control for ~24 weeks during pregnancy. FITT-V metrics were analyzed from session records. Infant mesenchymal stem cells (MSCs), a model of infant adiposity, were collected from umbilical cord at delivery, adipogenically differentiated, and stained for lipids. Infant body fat percentage was estimated from skinfolds measured at one month of age.

Results: Higher weekly exercise volume correlated with lower infant body fat (R² = .12, p = .03) and MSC lipids (R² = .13, p = .01). Weekly exercise frequency (R² = .06, p = .10) and total volume (R² = .19, p = .002) influenced adiposity. Supscapular skinfolds were notably affected by exercise (R² = .27, p < .001).

Conclusions: In utero exposure to exercise beyond minimum recommendations is associated with reduced infant adiposity. Specifically, our findings suggest exercising below 450 MET*minutes per week, e.g., exercising at an average of 3 METs for 150 minutes per week, or 5 METs for 90 minutes per week, excludes individuals from these offspring health benefits.

Background: Heart failure (HF) is characterised by altered skeletal muscle morphology. The aim of this systematic review and meta-analysis was to explore cross-sectional differences in muscle morphology and metabolism between patients with HF and healthy controls. Methods: A literature search of studies was conducted from inception to February 2025 across PubMed, Scopus, Web of Science, and the Cochrane Library. Eligible studies compared skeletal muscle morphological differences via the vastus lateralis from patients with HF vs. healthy controls. A meta-analysis was conducted using the random effects inverse-variance model. Results: Thirty-five studies were included in this study. Patients with HF displayed similar absolute muscle fiber areas (type I, II, IIa, IIx), lower relative type I fiber area (MD: -8.3%, 95% confidence interval (95% CI): -12.3 to -4.4), and higher type II (MD: 11.3%, 95% CI: 7.3 to 15.4) and IIx areas (MD: 7.4%, 95% CI: 4.3 to 10.4) vs. healthy controls. Capillaries per fiber were reduced in HF (MD = -0.28, 95% CI: -0.52 to -0.03), particularly for type IIa (MD = -0.30, 95% CI: -0.54 to -0.06) and IIx fibers (MD = -0.35, 95% CI: -0.55 to -0.15). IGF-1 was lower (-19.4 mRNA AU, 95% CI: -36.3 to -2.5), and myostatin was elevated (16.1 mRNA AU, 95% CI: 2.9 to 29.2) in HF. Citrate synthase, 3-hydroxyacyl-CoA-dehydrogenase, and succinate dehydrogenase were significantly lower in HF (p < 0.05). Conclusions: In HF, reduced relative type I fiber area, increased type II/IIx, reduced capillarization, altered anabolic/catabolic markers, and impaired energy metabolism enzymes, were observed compared to controls.

Background: Neurological injury, the leading cause of death after cardiac arrest resuscitation, has been shown to worsen progressively in the post-cardiac arrest period. This deterioration may be due to impaired cerebral autoregulation, leading to harmful alterations in cerebral perfusion. We aimed to investigate the myogenic response, a key component of cerebral autoregulation, in the post-cardiac arrest period. Method: Rats were anesthetized, intubated, catheterized, and randomized into a sham group or cardiac arrest group. Cardiac arrest rats underwent 7 minutes of cardiac arrest. Subsequently, groups were observed for 4 hours. Middle cerebral arteries (MCAs) were examined utilizing pressure myography and confocal microscopy. qPCR was performed on the posterior communicating arteries. Results: The myogenic response to increasing levels of intraluminal pressure was significantly reduced in MCAs from cardiac arrest rats compared with sham (p=0.02, mixed model for repeated measures). The MCAs demonstrated comparable contraction to increasing concentrations of U46619, but a high K⁺ solution yielded significantly lower vasoconstriction in cardiac arrest MCAs compared with sham (sham: 152±5 µm and cardiac arrest: 166±3 µm, p=0.03). qPCR showed reduced gene expression of cytoplasmic tyrosine kinase ABL1, rho-associated protein kinase 1, and endothelial NO synthase in cerebral arteries from cardiac arrest rats compared with sham. Confocal microscopy revealed no significant differences in nitrotyrosine or F-actin expression between groups in MCAs. Conclusion: In rat MCAs, the myogenic response, myogenic tone, and the maximum contraction are significantly reduced 4 hours after cardiac arrest. Our results suggest impaired calcium-sensitizing mechanisms in cerebral myogenic vasoconstriction after cardiac arrest.

The genioglossus (GG) muscle of the tongue, innervated by hypoglossal motoneurons, plays a critical role in the pathophysiology of obstructive sleep apnea. The state-dependent activity of the hypoglossal motoneurons is largely maintained by excitatory noradrenergic drive. However, this drive was hypothesized to be mediated by unidentified peri-hypoglossal neurons. We used microinjections of phenylephrine or prazosin, α1-adrenoceptor agonist and antagonist, respectively, into the medullary reticular formation rostral to the hypoglossal nucleus to locate these neurons. The phenylephrine or prazosin were microinjected into the hypoglossal nucleus and into rostral medullary regions while recording spontaneous activity in GG and diaphragm muscles in anesthetized C57bl/6J mice. The microinjections of phenylephrine/prazosin elicited respectively excitatory/inhibitory responses in the GG muscle, which had minimal latencies when injected into a limited region just rostral to the hypoglossal nucleus, which we termed the "pre-hypoglossal region" (PHR). In isoflurane-anesthetized mice, phenylephrine injected into the PHR induced large increases in GG muscle activity (21.8 ± 3.5 vs. baseline 4.50 ± 0.86, arbitrary units). These phenylephrine-induced responses from the PHR were substantially stronger compared to those evoked from the hypoglossal nucleus (5.46 ± 1.3 vs. baseline 4.12 ± 0.73). However, in ketamine/xylazine-anesthetized mice, phenylephrine's ability to activate the GG muscle from the PHR was substantially blunted, which suggests that the ketamine-induced systemic antagonism of glutamatergic NMDA receptors may interfere with the response. Our findings suggest that the PHR contains interneurons that mediate the state-dependent noradrenergic drive to hypoglossal motoneurons, and that glutamate may be used as mediator by PHR circuitry.

The upper limits for total energy expenditure (TEE) and water turnover (rH₂O) in humans have been reported during several continuous single-day ultra-endurance races (running, cycling, triathlon). Currently, the upper limits for TEE and rH₂O during continuous single-day activity in cold weather (<0C) remain unknown. The Arrowhead Ultra is one of the coldest ultra-endurance races in North America and provides a unique opportunity to answer these questions. Racers select a bicycle, cross-country skis, or foot travel to traverse a 214km snow-covered trail (altitude range 345-426m, 2,030m elevation gain). Historically, ~1/2 of the racers complete the event. In this case study, we assessed TEE and rH₂O from the racer (cyclist, age:22yrs, height:1.84m, body mass:87.7kg, VO_2max:5.0LO₂.min^-1) who won the 2025 Arrowhead Ultra (17.9hr, ^-13-^-1C) using the doubly labeled water method. Total energy and fluid intake were recorded to assess energy and fluid balance. Mean heart rate was 141bpm (71% of maximum heart rate). TEE was 63.9MJ (15,273kcals, 9.6x basal metabolic rate) while total energy intake was 33.2MJ (7,941kcal). Mean carbohydrate intake was 88g.hr^-1. Water turnover was 17.7L yielding a rH₂O/TEE ratio of 0.28L.MJ^-1 for the race. The cyclist demonstrated high TEE and rH₂O that were comparable to values from other ultra-endurance athletes competing in a range of temperatures (3-34C). Notably, rH₂O from this cyclist was higher compared to athletes performing other ultra-type endeavors in cold weather conditions (^-25-^-19C). Our observations shed light on energy and fluid demands during continuous single-day activity in the cold and have endurance training and performance implications.

In Acute Respiratory Distress Syndrome (ARDS), regional aeration is often gravity-dependent, with Positive End-Expiratory Pressure (PEEP) recruiting the lung dorsally. While recruitability can be assessed globally, our aim was to determine the impact of PEEP on regional recruitability and regional strain. To achieve a large representation of recruitability, we studied two preclinical porcine models of acute lung injury ([ALI] 19 symmetrical and 10 asymmetrical ALI), 20 patients with ARDS of mixed etiology (mixed ARDS) and 15 with COVID-19 ARDS. All study subjects underwent a single-breath derecruitment maneuver from high to low PEEP to quantify recruitability using the recruitment-to-inflation ratio (R/I). The regional effects of PEEP on strain were assessed using Electrical Impedance Tomography (EIT). Symmetrical ALI animals had the highest R/I (1.39[1.04-1.66]), followed by mixed ARDS (1.06[0.70-1.23]), COVID-19 ARDS (0.66[0.51-0.98]), and asymmetrical ALI (0.45[0.22-0.85]). Dorsal regions had the highest recruitability (p=0.001), and differences between dorsal and ventral regions were higher in recruitable subjects. Increasing PEEP decreased ventral dynamic strain (p<0.01), with varying effects on dorsal dynamic strain. A paradoxical increase in dorsal dynamic strain associated with ventral hyperinflation could be observed across all groups, but more frequently in the less recruitable subjects. It was predicted by the EIT ventral-to-dorsal shift in ventilation normalized to the change in dorsal lung volume (p<0.001). In animals and patients with varying recruitability, a higher global R/I is associated with a higher effect on the dorsal versus ventral R/I. PEEP can paradoxically increase dorsal strain due to ventral overdistention, and this is detectable by EIT.

Despite the evidence that responses to intermittent hypoxia (IH) vary between sexes, potentially underlying sex-specific comorbidities of sleep apnea, the roles that sex hormones play during exposure to IH in rodent models remain poorly defined. The Estradiol receptor ɑ (ERɑ), expressed in structures of the peripheral and central nervous system, contributes to autonomic regulations and control of arterial blood pressure, accordingly, we tested the hypothesis that ERα modulates respiratory and heart rate variability in male and female mice exposed to IH. We used adult wild-type (WT) and ERα knockout (ERαKO) mice of both sexes for whole-body plethysmography, arterial blood pressure and ECG recordings before and after 14 days of IH (6% O₂, 12 cycles/h, 12 h/day). Compared to males, WT females exhibited greater respiratory variability and higher apnea frequency before IH exposure. In females, ERα deletion increased body weight, and reduced post-sigh apnea frequency before IH exposure. In ANCOVA/GLM models, body weight was a significant negative covariate for post-sigh and spontaneous apneas before IH exposure, while sex and genotype effects were not significant after adjustment. IH exposure increased the mean and diastolic blood pressures only in WT males. IH also increased apneas frequency in WT females, an effect markedly reduced by ERɑ deletion. Similarly, heart rate variability increased in WT females following IH, reflecting enhanced parasympathetic modulation, an effect absent in ERαKO females and in WT or ERαKO males. We conclude that in female mice, deletion of ERα prevents IH-induced improvement of heart rate variability.