Journal of applied physiology最新文献

Neonatal inflammation is common and has lasting detrimental consequences for the health of the adult nervous system, including on the neural control of breathing. Our previous work demonstrated that neonatal inflammation abolished adult respiratory motor plasticity; yet, the mechanisms underlying this impairment or the broader impact of neonatal inflammation on control of breathing were unknown. Since microglia are key immune cells in the brain and contribute to lasting sex-specific disruptions in nonrespiratory behaviors, we hypothesized that neonatal inflammation would induce lasting sex-dependent activation of adult microglia in respiratory control regions and contribute to broader breathing impairments. In support of this hypothesis, neonatal inflammation increased adult male medullary microglia number and TNF-α gene expression. In adult females, microglia number was unchanged, but neonatal inflammation increased female medullary microglial IL-6 gene expression. Surprisingly, changes in adult microglia were confined to the medulla and cortex, with no changes in ventral cervical spinal microglia, suggesting that the origins of impaired respiratory motor plasticity after neonatal inflammation are likely outside the spinal cord. Neonatal inflammation also augmented adult male hypercapnic ventilatory responses and hypoxic ventilatory responses, and decreased sighs in females, consistent with neonatal inflammation increasing adult risks for ventilatory control disorders. Thus, lasting increases in microglia number and inflammatory gene expression likely contribute to abolished adult respiratory motor plasticity after neonatal inflammation, with distinct inflammatory mechanisms likely underlying abolishment in males and females.NEW & NOTEWORTHY Neonatal inflammation is common, yet our understanding of the mechanisms underlying impairment is poorly understood. Here, we demonstrate for the first time that adult medullary microglia sex- and region-specifically contribute to lasting adult inflammation after neonatal inflammation. Sex-specific activation of adult medullary microglia emphasizes that distinct inflammatory mechanisms underlie male versus female impairments in respiratory control after neonatal inflammation. Such lasting microglia activation likely contributes to abolished adult respiratory motor plasticity and chemoreflexes after neonatal inflammation.

Heart failure (HF) is a complex clinical syndrome characterized by exercise intolerance. However, most diagnostic assessments are performed at rest, when many patients are asymptomatic. To better understand the underlying pathophysiology, examination during exercise is needed. Hydraulic force, a newly identified mechanism of diastolic filling, is proportional to the difference in short-axis areas between the left ventricle and atrium, known as the atrioventricular area difference (AVAD). Although hydraulic force has been shown to augment diastolic filling during exercise in healthy individuals, its role in HF during exercise remains unexplored. This study aimed to investigate whether hydraulic forces impair or augment diastolic filling in patients with HF during exercise, using AVAD measurements from exercise cardiovascular magnetic resonance (CMR) imaging. We examined 13 healthy volunteers and 22 patients with HF at rest and during exercise using a CMR-compatible ergometer. AVAD was measured at end-systole (ES) and end-diastole (ED). In patients with HF, AVAD at ED decreased during exercise (from 17 ± 5 cm² to 15 ± 6 cm², P = 0.006), whereas it increased in healthy volunteers (from 16 ± 3 cm² to 17 ± 3 cm², P = 0.014). AVAD at ES decreased in both HF (from -2 ± 5 cm² to -8 ± 5 cm², P < 0.001) and healthy volunteers (from -3 ± 2 cm² to -5 ± 3 cm², P = 0.011). In conclusion, the results suggest impaired diastolic function during exercise in HF through reduced hydraulic force compared with rest. These findings provide new mechanistic insights and may partly explain the hallmark symptom of exercise intolerance in heart failure.NEW & NOTEWORTHY Hydraulic force is a newly identified mechanism of diastolic function. This study is the first to assess hydraulic forces in patients with heart failure during exercise using cardiovascular magnetic resonance. In contrast to healthy individuals, hydraulic force decreased from rest to exercise in patients with heart failure, suggesting impaired diastolic filling. These findings offer new mechanistic insights into diastolic dysfunction during exercise and may help explain the hallmark symptom of exercise intolerance in heart failure.

Spending a single night at moderate altitude before ascending to high altitude may enhance ventilatory acclimatization but also exacerbate sympathetic activation, a response that should be carefully pondered in persons with coronary artery disease (CAD). Ten males with CAD participated in this randomized placebo-controlled crossover trial in a hypobaric chamber, where they slept either at simulated 1,900 m (intervention) or in control conditions (250 m, placebo) before being decompressed to 3,000 m the following morning. Respiratory polygraphy was performed each night. Peripheral oxygen saturation ([Formula: see text]), end-tidal partial pressure of CO₂ ([Formula: see text]), cerebral tissue oxygen saturation index (cTSI), baroreflex sensitivity (BRS), heart rate variability (HRV), and pulmonary artery systolic pressure (PASP) were recorded during wakeful rest each morning, both before the overnight stay (at 250 m) and after the simulated ascent to 3,000 m. The intervention night was associated with a greater number of apneas/hypopneas (33 [9, 51] h^-1) than placebo (6 [3, 13] h^-1, P = 0.02). At 3,000 m, [Formula: see text] was higher after intervention (88 ± 2%) than placebo (87 ± 2%, P = 0.03), [Formula: see text] was lower after intervention (34 ± 3 mmHg) than placebo (36 ± 3 mmHg, P = 0.002), cTSI decrease was smaller after intervention (-3.6 ± 2.2%) than placebo (-6.5 ± 3.1%, P = 0.02), and PASP was higher after intervention (30 ± 8 mmHg) than after placebo (28 ± 7 mmHg, P = 0.04), whereas BRS and HRV indices showed no differences. We conclude that a single night at 1,900 m is sufficient to trigger measurable ventilatory acclimatization in persons with CAD without altering BRS and HRV at 3,000 m, but likely enhancing pulmonary hypoxic vasoconstriction.NEW & NOTEWORTHY We found that a single night spent at simulated moderate altitude (1,900 m) prompts measurable ventilatory acclimatization when ascending to simulated high altitude (3,000 m) in males with coronary artery disease. We also found that, although sleeping at 1,900 m increases the occurrence of apneas and/or hypopneas, this did not modify heart rate variability and baroreflex sensitivity responses at 3,000 m.

Extracellular heat shock protein 70 (HSP70) acts as a damage-associated molecular pattern, or "danger signal" for the immune system. Acute prolonged exercise evokes various physiological stresses that can stimulate the release of extracellular HSP70. However, exercise-induced extracellular HSP70 responses are inconsistent in human studies. Therefore, the purpose of this meta-analysis and meta-regression was to systematically evaluate the effect of exercise on plasma HSP70 expression and to determine the exercise-associated factors contributing to plasma HSP70 response. Data were extracted from 26 experimental trials from 13 studies, including 154 participants, in which plasma HSP70 was measured before and after prolonged, continuous running or cycling exercise at a fixed intensity relative to V̇o_2max. Meta-analysis was performed to determine the raw mean difference (MD) between post- and pre-exercise HSP70 concentration. Meta-regression was performed to establish the moderating effects of V̇o_2max, exercise intensity, duration, modality, environmental temperature, humidity, and hypoxia on the plasma HSP70 response. There was a significant effect of exercise on plasma HSP70 concentration (MD = 0.73 ng·mL^-1, 95% CI [0.13, 1.34], P = 0.02). Meta-regression explained ∼57.1% of variation in exercise-induced change in plasma HSP70 concentration (marginal R² = 0.571). The V̇o_2max (β = 0.51, 95% CI [0.03, 1.00]), exercise duration (β = 0.43, 95% CI [0.21, 0.65]), intensity (β = 0.40, 95% CI [0.08, 0.73]), and environmental temperature (β = 0.27, 95% CI [0.10, 0.43]) explained variation in the plasma HSP70 response. These data contribute to our understanding of the factors that modulate the plasma HSP70 response to acute prolonged exercise.

Inspiratory muscle fatigue develops during exercise before intolerance. The expiratory muscles are less resistant to fatigue compared to the inspiratory muscles, but the time course of inspiratory and expiratory muscle fatigue during exercise has not been compared. Ten healthy adults (25 ± 5 yr; 2 females) cycled on three separate occasions at 25% of the difference between estimated critical power and peak ramp incremental power (severe intensity domain) for 1) 100% of time to the limit of tolerance (T_LIM; 10.2 ± 2.6 min); 2) 75% T_LIM (7.7 ± 1.9 min); and 3) 50% T_LIM (5.1 ± 1.3 min). Expiratory and inspiratory muscle fatigue were quantified as the pre- to postexercise reduction in the gastric (Pga_tw) and diaphragm (Pdi_tw) twitch pressure response to magnetic stimulation of the thoracic and cervical nerves, respectively. Pga_tw and Pdi_tw were reduced from baseline values after 50% T_LIM (11.9 ± 8.2% and 9.5 ± 9.2%; both P < 0.05). The magnitude of expiratory and inspiratory muscle fatigue increased progressively at 75% T_LIM (20.0 ± 12.6% and 15.2 ± 10.1%; both P < 0.05) and 100% T_LIM (30.3 ± 15.6% and 22.4 ± 12.5%; both P < 0.05), but there was no difference between muscle groups (P > 0.05). Expiratory and inspiratory muscle fatigue develops relatively early during severe intensity exercise and increases progressively in magnitude by exercise intolerance. The onset and progression of respiratory muscle fatigue during exercise are not different between the expiratory and inspiratory muscles.NEW & NOTEWORTHY During severe exercise, expiratory and inspiratory muscle fatigue develops by ∼50% of the tolerable exercise duration. The magnitude of expiratory and inspiratory muscle fatigue increases progressively toward exercise intolerance but is not different between muscle groups; this is despite the expiratory muscles being less fatigue-resistant. Inspecting esophageal and gastric twitches via cervical stimulation, we speculate that the progressive magnitude of exercise-induced inspiratory muscle fatigue is a function of recruitment and fatigue of the accessory inspiratory muscles.

Autonomic cardiovascular control is often disrupted following a spinal cord injury (SCI), resulting in impaired autonomic cardiac regulation and hemodynamic instability. A systematic preregistered review following existing guidelines was undertaken to evaluate the effect of exercise training on noninvasive measures of autonomic cardiovascular control, including orthostatic intolerance, blood pressure variability (BPV), baroreflex function, and heart rate variability (HRV) in adults with SCI. Seven databases were searched from inception to October 2025. Experimental studies (randomized controlled trials, nonrandomized controlled trials, or pre-post studies) consisting of exercise interventions of ≥2 wk evaluating measures of orthostatic tolerance, BPV, baroreflex function, and/or HRV in adults (≥18 yr old) with SCI were included. Risk of bias and study quality were assessed. Of 1,208 unique records identified, 16 studies (329 participants) were included: 8 randomized controlled trials, 3 nonrandomized controlled trials, and 5 pre-post studies. Five of seven studies reported no change in orthostatic intolerance following exercise training, whereas three of five studies found no changes in power spectral analysis of BPV. Conversely, all five studies reporting baroreflex outcomes found improved function, with enhanced cardiovagal baroreflex sensitivity or effectiveness index after training. The 13 studies assessing autonomic cardiac control through HRV reported mixed results, irrespective of whether time- or frequency-domain analyses were used. This review provides preliminary evidence that exercise training can improve baroreflex function in adults with SCI. However, current evidence remains inconclusive regarding whether exercise training can improve HRV, BPV, and the ability to tolerate postural stress and thus prevent orthostatic hypotension.

Despite the critical role of persistent inward currents (PICs) in modulating motor neuron output, and thus neuromuscular performance, it remains unknown whether their contribution to motor neuron discharge behavior varies throughout the day. This study aimed to determine whether PIC-related effects on motor neuron activity during submaximal dorsiflexion tasks differ between the early morning and late afternoon. Eighteen healthy adults (4 females; 27.4 ± 5.6 yr) performed triangular isometric contractions at two randomized time-points on separate days: early morning (7:00-8:30 AM) and late afternoon (5:00-7:30 PM). Two conditions were tested: 1) a relative condition, where the target force corresponded to 40% of the maximal voluntary force (MVF) measured during that session, and 2) an absolute condition, where the target force was 40% MVF recorded during the first session. High-density surface electromyography signals were recorded from the tibialis anterior and decomposed into motor unit spike trains. The prolongation effect of PICs, estimated via ΔF, was significantly greater in the late afternoon in both the relative-absolute force conditions. The amplification effect of PICs, estimated by the acceleration phase of the discharge trajectory, was higher in the late afternoon, but only in the relative force condition. Brace height did not differ between morning and afternoon, but attenuation was lower in the late afternoon during the relative force condition. Collectively, these findings suggest a time-of-day modulation of PIC contribution to motor neuron discharge behavior, likely mediated by a change in inhibitory-excitatory balance between early morning and late afternoon rather than by changes in neuromodulatory drive.NEW & NOTEWORTHY Although human neuromuscular performance often peaks in the late afternoon, this pattern may not arise solely from peripheral mechanisms. This study provides evidence for a modulation in the contribution of persistent inward currents (PICs) to motor neuron discharge behavior between early morning and late afternoon. PIC-related estimates indicate a modest enhancement of motor neuron excitability in the late afternoon, likely explained by a change in the inhibitory-excitatory balance rather than by changes in neuromodulatory drive.

Cervical spinal cord injury (SCI) removes descending sympathetic control over the heart and vasculature, which alters cardiovascular function. Ventricular-arterial coupling (VAC) provides insight into the heart's mechanical and energetic efficiency by evaluating the interaction between cardiac contractility (end-systolic elastance; Ees) and arterial elastance (Ea). This study investigated VAC in nonathletes (SCI-NA) and athletes (SCI-A) with cervical SCI, and able-bodied (AB) controls. We additionally validated noninvasive estimation of Ees with catheter-derived assessments in rodents with SCI. Data were collected on SCI-NA (9 M, 2 F), SCI-A (12 M, 2 F), and AB (10 M, 5 F) individuals. Cardiac contractility was estimated using single-beat Ees_(sb) and an alternative assessment of contractility derived from the left ventricle outflow tract [contractility_(LVOT)]. Ea was determined with the standard Simpson's biplane method [Ea_(Simp)] and with Doppler [Ea_(Doppl)]. VAC was determined for each method as: VAC_(sb) = Ea_(Doppl)/Ees_(sb) and VAC_(LVOT) = Ea_(Simp)/contractility_(LVOT). Associations between contractility_(LVOT) and catheter Ees in rats were assessed with linear regression and intraclass correlation coefficient (ICC). Compared with AB, contractility_(LVOT) was lower in SCI-NA (P < 0.001) and SCI-A (P = 0.04). Ea_(Simp) was higher in SCI-NA versus SCI-A and AB (all P < 0.01). As such, SCI-NA exhibited a higher VAC_(LVOT) versus AB (P < 0.001) and SCI-A (P = 0.002). In rodents, we found excellent agreement between contractility_(LVOT) and Ees (ICC 0.880; P = 0.002). SCI-NA exhibit an elevated VAC due to lower contractility_(LVOT) and higher Ea, suggesting an uncoupling of the heart and vasculature. SCI-A exhibit preserved VAC despite a lower contractility_(LVOT) than AB, suggesting that chronic exposure to exercise maintains coupling between the heart and vasculature.NEW & NOTEWORTHY The present study provides the first demonstration that VAC is impaired in humans with SCI, which may further contribute to the poor exercise tolerance often observed in this population. Our findings in the SCI-A group imply that chronic exposure to exercise increases VAC, suggesting that adherence to a long-term exercise program may optimize ventricular-vascular interaction postinjury.

An initial bout of eccentric exercise (EE) is known to protect against exercise-induced muscle damage (EIMD) following the performance of a subsequent bout of similar volume and intensity, a phenomenon known as the repeated bout effect (RBE). We examined whether aspects of motor unit (MU) behavior and reticulospinal tract (RST) drive are neural components of this protective effect. Twenty-three participants (6 females; age 26 ± 5 yr) performed two bouts of EE (10 repetitions × 10 sets) with the dorsiflexors separated by 3 wk. Maximal voluntary isometric torque (MVIC), muscle soreness (DOMS), MU behavior (quantified from MUs identified via high-density electromyography decomposition), and RST drive (visual-auditory vs. visual-startle reaction time) were recorded at baseline, 24, 48, and 72 h postexercise. Symptoms of EIMD were elevated following bout 1; MVIC was reduced, and perceived soreness was increased. Despite comparable work performed (∼1,300 J; P = 0.721), MVIC (P < 0.001) and soreness (P < 0.001) recovered quicker following bout 2. The attenuated symptoms of EIMD were coupled with reduced variability in MU discharge rate (P = 0.001) and torque (P < 0.001). MU adjustments were not accompanied by any change in RST drive (-8 ms; P = 0.634). Lower MU discharge variability and an attenuated increase in firing rate in bout 2 support a neural contribution to the RBE. The present study cannot infer whether such adaptations actively protect against muscle damage or merely reflect the reduced mechanical and nociceptive disturbance. Nonetheless, we confirm that MU adjustments are involved in the RBE phenomenon.NEW & NOTEWORTHY Unfamiliar eccentric exercise causes muscle damage, but repeating the same exercise later substantially reduces symptoms-an adaptive phenomenon known as the repeated bout effect (RBE). We investigated the neural contributions to this response. We observed lower motor unit discharge variability and smaller increases in firing rate after the repeated bout. These findings provide evidence that motor unit-level neural adjustments are a critical component of the RBE, offering a new perspective on this protective adaptation.

Acute kidney injury (AKI) contributes to excess hospital admissions observed during heatwaves. We tested the hypothesis that water spray and fan use would modulate biomarkers of AKI risk in older adults exposed to 3 h of very hot and dry heat. On each of 3 days (randomized), older adults (12 males/8 females; 66-84 yr) were exposed to 3 h of heating (47°C, 15% relative humidity) with no cooling intervention (control), water spray, or fan use. We assessed core temperature, fluid loss, biomarkers of AKI risk (AKIRISK score), and kidney function (plasma creatinine and cystatin C). The increase in core temperature was 1.3 ± 0.5°C (means ± SD) in control, 1.0 ± 0.2°C in water spray, and 1.9 ± 0.7°C in the fan trial. Fluid loss was 0.9 ± 0.2% in control, 0.4 ± 0.2% in water spray, and 1.5 ± 0.4% in fan. Compared with control, the AKIRISK score at end-heating was -0.18 [95% CI: -0.35, -0.02] lower in water spray (P = 0.047) and 0.26 [0.09, 0.44] higher in fan (P = 0.002). Repeated-measures correlations demonstrated positive associations between end-heating core temperature (r = 0.77; P < 0.001) and fluid loss (r = 0.48; P = 0.001), both relative to the end-heating AKIRISK score. Compared with control, end-heating plasma creatinine was not different (P = 0.43), but plasma cystatin C was 0.07 [-0.13, -0.01] mg/L lower (P = 0.025) in water spray. Compared with control, end-heating creatinine was 0.08 [0.03, 0.12] mg/dL higher (P < 0.001), and cystatin C was 0.07 [0.01, 0.13] mg/L higher (P = 0.026) in the fan trial. These findings suggest that in very hot and dry conditions, water spray can attenuate, whereas fans elevate heat-related increases in AKI risk biomarkers.NEW & NOTEWORTHY Acute kidney injury contributes to the increased mobility and mortality reported during heatwaves. Air conditioning is protective but may not be available to all; thus, there is a need to identify non-air-conditioning-dependent cooling strategies. We show that water spray mitigates, but fans elevate heat-related increases in biomarkers of acute kidney injury in older adults exposed to 3 h of very hot and dry conditions.