American journal of physiology. Regulatory, integrative and comparative physiology最新文献

Aging from young to middle-aged and older adulthood modulates sweating differently across body regions, yet how biological aging from young adulthood to the 80s and beyond affects cholinergic sweating remains unclear. A total of 248 participants (143 males and 105 females) were grouped as young (≥18 + 20s), middle-aged (30s + 40s + 50s), older (60s + 70s) adults, and elderly (80s + 90s). Acetylcholine-induced sweat rate, activated sweat gland density, and sweat gland output were assessed via transdermal iontophoresis. Forearm sweat rate declined in the 30s + 40s + 50s and older in males and the 60s + 70s and older in females, compared with the ≥18 + 20s group (all P ≤ 0.006). Thigh sweat rate also declined with aging and was further reduced in the 60s + 70s and 80s + 90s compared with the 30s + 40s + 50s group in males (both P ≤ 0.035). Sweat rate did not differ between the 60s + 70s and 80s + 90s groups in either region or sex (all P ≥ 0.677). Sex differences in forearm sweat rate persisted across all age groups (all P ≤ 0.012) but diminished on the thigh in the 60s + 70s and 80s + 90s groups (both P ≥ 0.183). These changes were attributed to reductions in sweat gland output in males and combined reductions in sweat gland density and output in females. Collectively, forearm cholinergic sweating declines from the 30s + 40s + 50s to the 60s + 70s relative to young adults but shows minimal further attenuation beyond the 70s in both sexes. Thigh cholinergic sweating function is more affected by biological aging in males. We also highlight the characteristics of sweating in two participants in their 90s, providing insights into sweating function at the end of the lifespan.NEW & NOTEWORTHY The effects of biological aging and sex on cholinergic sweating across the lifespan, especially beyond 80, remain poorly understood. We demonstrate that forearm cholinergic sweating declines from the 30s to 70s compared with young adults, with minimal further attenuation beyond the 70s in both sexes. In contrast, thigh sweating is more strongly impacted by aging in males. Data from 90-yr-old participants provide valuable insights into sweating function near the end of their lifespan.

Noninvasive vagus nerve stimulation (VNS) devices promise stress-relief through increased parasympathetic activity and a more relaxed mental state, associated with heightened alpha wave electroencephalogram (EEG) activity. The cervical vagus nerve (CVN) contains five to six times more Aβ-fibers than the auricular branch of the vagus nerve (ABVN). In addition, the CVN contains afferent and efferent fibers, whereas the ABVN is a purely afferent nerve. We hypothesized that hemodynamic, autonomic, and cerebral responses to cervical VNS are more pronounced than those to auricular VNS. Young healthy adults were randomized into a time control (n = 10), a bilateral cervical VNS (n = 9, 41 Hz, 100 μs, <40 mA), and two unilateral auricular VNS (10 Hz, 300 μs, 2-3 mA) groups with electrodes at the cymba conchae (n = 7) or tragus (n = 9) of the right ear. Systolic blood pressure (SBP) decreased only during cervical VNS (baseline: 134 ± 15 mmHg vs. VNS: 120 ± 16 mmHg, means ± SD, n = 9, P < 0.05), which was associated with decreased low-frequency (LF) SBP variability (baseline: 17.1 ± 9.1 mmHg² vs. VNS: 7.8 ± 9.1 mmHg², means ± SD, n = 9, P < 0.05). Cervical but not auricular VNS was followed by increased alpha wave activity (baseline: 6.2 ± 1.8 μV vs. VNS: 7.7 ± 1.7 μV, means ± SD, n = 9, P < 0.05) recorded from the FP1 EEG electrode position. In conclusion, the hemodynamic, autonomic, and EEG responses to acute bilateral cervical VNS are more pronounced than those of unilateral auricular VNS, potentially, because the CVN contains five to six times more Aβ-fibers than the ABVN. Reduced SBP and LF SBP variability together with increased EEG alpha wave activity may indicate a more relaxed mental state during cervical VNS.NEW & NOTEWORTHY Acute application of noninvasive bilateral transcutaneous cervical vagus nerve stimulation caused a reduction in systolic blood pressure, associated with a decrease in low-frequency systolic blood pressure variability. Furthermore, cervical vagus nerve stimulation increased alpha wave EEG activity. These responses may indicate a more relaxed mental state during cervical VNS.

Cardiomyocytes undergo proliferation, differentiation, and hypertrophy during fetal development. Current techniques struggle to distinguish cardiomyocyte proliferation from alternative cell fates. In this study, we combined flow cytometry measures of cardiomyocyte ploidy (DAPI) and in vivo DNA replication (EdU) over a 24-h period to evaluate the trajectories of cardiomyocytes from normally growing control fetal sheep and fetuses affected by placental insufficiency and fetal growth restriction (FGR) at 0.9 gestation. We categorized ∼100,000 cardiomyocytes from the left and right ventricles (LV and RV) of each animal as proliferating (2C EdU⁺), differentiated (4C EdU^-), or endoreplicating and polyploid (6C+ EdU⁺). Compared with controls, FGR hearts had 25%-50% fewer cardiomyocytes that replicated DNA (EdU⁺) (LV: P = 0.02, RV: P = 0.002). The fraction of proliferating cardiomyocytes, indicated by the population of newly synthesized 2C EdU⁺ daughter cells, was ∼20% lower in FGR fetuses (LV: P = 0.006, RV: P = 0.02). Instead, the percentage of endoreplicating cardiomyocytes (6C+ EdU⁺) in FGR hearts was double that of controls (LV: P = 0.004, RV: P = 0.002). Although total EdU⁺ was not a strong predictor of cardiac growth, LV and RV mass correlated positively with the percentage of 2C EdU⁺ cardiomyocytes and negatively with 6C+ EdU⁺ cardiomyocytes across all fetuses. LV mass also correlated positively with the percentage of differentiated cardiomyocytes (4C EdU^-), which was lower in FGR hearts compared with controls (P = 0.008). This study is the first to characterize cardiomyocyte fate following DNA replication in fetal sheep. Our findings suggest that FGR cardiomyocytes differentially prioritize their cycling capacity in favor of polyploidization instead of proliferation.NEW & NOTEWORTHY Knowledge of cardiac development has been limited by available methodologies. We used a novel flow cytometry approach to measure DNA replication in utero and distinguish between cardiomyocyte proliferation, differentiation, and endoreplication in growth-restricted (FGR) and normally growing fetal sheep. FGR cardiomyocytes have lower proliferation rates but increased endoreplication compared with controls. Endoreplication and polyploidy are negatively correlated with ventricular mass. Our findings provide insight into fetal cardiac development and how cardiomyocyte fate is altered by FGR.

Diving marine mammals must allocate time between respiring at the surface and foraging underwater. Previous studies of optimal diving theory have attempted to predict such patterns, but the amount of time divers must spend at the surface before and after dives of varying durations remains difficult to assess. Here, we examined the surfacing and breathing patterns of short-finned pilot whales (Globicephala macrorhynchus) from biologger data to examine their use of anticipatory versus reactive strategies. We used linear mixed-effects models to examine the effect of dive characteristics on surface interval (SI) durations and breathing rate. Pilot whales increased SI duration before dives of increasing duration and after dives of increasing activity. Instantaneous breathing rates (f_Rs) of pilot whales demonstrated little anticipation but rather a strong reactive pattern seen by the modulation of f_R in response to the previous rather than upcoming dive. During typical SIs, f_R was predicted by time since previous dive, duration of the previous dive, time until upcoming dive, and activity of the previous dive. Short-finned pilot whales in our study area exhibit both benthic and pelagic foraging, which may compel anticipation when prey capture is predictable and reaction when prey capture is difficult to predict. The observed surfacing and breathing patterns therefore likely reflect a balance of the needs for blood gas homeostasis, aerobic metabolism, and the variability of foraging opportunities. An improved understanding of how animals make decisions about diving is critical for informing predictions of how they will contend with changing ocean landscapes.NEW & NOTEWORTHY A new study reveals how short-finned pilot whales balance the conflicting demands of foraging underwater with breathing at the surface. Using data from digital tags, scientists found that pilot whales rely more on surfacing strategies that react to the effort of a dive rather than anticipate. Their use of such strategies may reflect variation in the ability to predict prey capture in benthic and pelagic habitats.

Maternal obesity increases the risk of preterm delivery and rapid transition of offspring from a hypoxemic environment to a normal or elevated oxygen environment, especially if the baby receives oxygen therapy. Maternal obesity may also increase offspring risk of developing hypertension. Thus, we examined whether neonatal hyperoxia (HO) leads to elevated blood pressure (BP) in offspring from lean mothers and exacerbates adverse impact of maternal obesity on offspring BP regulation. Male and female Sprague-Dawley offspring from lean and high-fat diet-fed obese mothers (n = 12-18 mothers/group) were exposed to room air (∼21% O₂) or HO (80% O₂) between postnatal days P3 and P10 and then returned to room air. At 12 wk of age, offspring were instrumented with telemetry probes to measure BP and heart rate (HR). Contrary to our hypothesis, neonatal HO was associated with lower BP compared with control offspring from lean mothers (males: 105 ± 1 vs. 111 ± 1 mmHg; females: 102 ± 0.4 vs. 108 ± 0.4 mmHg) and also reduced BP and HR in hypertensive obese offspring from obese mothers (males: 117 ± 1 vs. 123 ± 1 mmHg and 351 ± 4 vs. 358 ± 5 beats/min; females: 113 ± 1 vs. 116 ± 1 mmHg and 376 ± 2 vs. 390 ± 4 beats/min). In lean offspring from lean mothers, neonatal HO was associated with reduced +dP/dt_max, whereas in obese offspring from obese mothers, HO attenuated cardiac dysfunction when compared with obese offspring not submitted to HO. These results suggest that exposure to HO in early postnatal life is not associated with elevated BP in early adulthood and it does not exacerbate the hypertensive effects of maternal obesity on offspring BP regulation.NEW & NOTEWORTHY Maternal obesity increases risk for preterm birth and neonatal oxygen exposure. We tested whether hyperoxia (80% O₂, P3-P10) worsens maternal obesity-induced hypertension. At 14 wk, BP measured by telemetry showed that hyperoxia unexpectedly lowered BP in lean and obese offspring and attenuated cardiac dysfunction in obese offspring. These findings indicate that neonatal hyperoxia does not exacerbate maternal obesity-induced hypertension and may mitigate early cardiac dysfunction.

The ability to withstand low and fluctuating oxygen levels is important for adipose tissue function. Hypoxia in mammalian cells typically stabilizes hypoxia inducible factor (HIF-1α) that alters downstream structural and metabolic pathways, which can have pathological consequences in humans and rodents. Gray seals (Halichoerus grypus) have extensive subcutaneous adipose as blubber, which naturally undergoes oxygen restriction acutely during diving and chronically during fattening. This study explored how blubber regulates responses to chemically induced pseudohypoxia. We obtained blubber biopsies from weaned pups (n = 6) and prepared explants that we incubated with or without cobalt chloride (CoCl₂), which stabilizes HIF-1α under normoxia. One explant per animal was immediately snap-frozen, and the remaining explants and media were collected every 2h. HIF-1α protein accumulation occurred rapidly in both control and CoCl₂-treated explants, peaking at 4h and 2h, respectively. HIF-1α mRNA increased in all explants. Mitochondrial complex I abundance increased in controls. CoCl₂ drove an additional increase in complex I, II and V proteins compared to controls at all time points. Surprisingly, Adiponectin and Ppar-γ were not downregulated. Collagen VI abundance increased 6h after treatment. Our results suggest that blubber explants experience hypoxia in culture, which is enhanced by chemical pseudohypoxia: CoCl₂ produced an additional impact on mitochondrial complex proteins. HIF-1α elevation in response to hypoxic challenge occurred earlier, to a greater extent but was shorter-lived than in other mammalian adipose. Our findings highlight potential differences in responses of seal blubber to hypoxia compared to human and rodent adipose.

Neurons in the nucleus of the solitary tract (NTS) are activated by inputs from the vagus nerve, including those from the gastrointestinal tract. This activation is relayed to CNS regions critical for the control of food intake. Changes to NTS neuron activation therefore impact the transmission of vagal information to the brain. Injection of neuropeptide Y (NPY) and the Y2 receptor agonist PYY-(3-36) into the dorsal vagal complex (DVC) containing the NTS increases food intake. However, how NPY produces this effect is not known. Here we use transgenic mice with EGFP expression driven by the tyrosine hydroxylase promoter (TH-EGFP) to identify NTS catecholamine neurons, as NPY terminals have been found in close proximity to NTS-TH neurons. We recorded from NTS TH-EGFP neurons in horizontal brain slices containing vagal afferents within the solitary tract (ST) using whole-cell patch-clamp techniques. NPY inhibited ST-evoked excitatory post synaptic currents (ST-EPSCs) in approximately two-thirds of TH-EGFP neurons. This effect was blocked by the Y2 receptor antagonist BIIE 0246 and mimicked by the Y2 agonist PYY-(3-36). In contrast, the Y1 receptor agonist L-P-NPY did not inhibit ST-EPSCs. NPY also reduced both basal and vagal-evoked action potentials in CA neurons. Finally, NPY attenuated the ability of the satiety peptide cholecystokinin (CCK) to increase glutamate release onto TH-EGFP neurons, an effect mimicked by PYY-(3-36). These results indicate that NPY inhibits both vagal- and CCK-induced activation of most NTS-TH neurons and suggest a potential mechanism for its effects to increase food intake at the level of the hindbrain.

Allostatic load, a maladaptive biological process wherein physiological stability ("allostasis") fails owing to chronic stress exposure, is traditionally measured by the allostatic load index (ALI). Whether ALI is associated with wearable-assessed physiological responses remains unknown. We aimed to determine the association between ALI and wearable-assessed physiological responses during a 10-wk military training course. Twenty-five participants (12 women) with ALI and suitable wearable data [84.31% complete data (range: 64.71%-97.56%)] were included. ALI (0-8) was calculated using biomarker components from neuroendocrine, autonomic, and immune systems. Device variables included total energy expenditure (TEE), energy expenditure during physical activity (PAEE), daytime heart rate (HR), sleeping HR, nonlinear HR variability (detrended fluctuation analysis, DFA-α₁), and sleep architecture. Flux was calculated as raw (Δ) or absolute difference (|Δ|) in average values between days and nights. Generalized linear mixed effect models assessed the association between high allostatic load (ALI > 4) and responses (α = 0.05). Twelve (4 women) participants experienced ALI > 4. High allostatic load was associated with TEE (β = 0.658, standard error (SE) = 0.002, odds ratio (OR) = 1.931, P < 0.001), Δ in relative PAEE (β = 0.472, SE = 0.002, OR = 1.602, P < 0.001), daytime HR (β = 0.189, SE = 0.002, OR = 1.208, P < 0.001), |Δ| in relative daytime HR (β = 0.262, SE = 0.001, OR = 1.298, P < 0.001), and |Δ| in relative sleeping HR (β = -0.048, SE = 0.001, OR = 0.953, P < 0.001). Every one-standard-deviation increase in absolute TEE, flux in relative PAEE, daytime HR, flux in daytime HR, and reduced flux in sleeping HR increased the risk of high allostatic load by 5%-90%. Chronically elevated and variable cardiometabolic activity with blunted night-to-night variation in sleeping HR may be a digital phenotype of high allostatic load in military personnel.NEW & NOTEWORTHY This investigation for the first time observed an association between the traditional measurement of allostatic load, the allostatic load index, and wearable-assessed physiological responses to strenuous military training stress. We found a novel digital phenotype of allostatic load characterized by chronically elevated and variable cardiometabolic activity with blunted variation in heart rate during sleep. This phenotype may serve as an at-risk profile of high allostatic load and prompt in-training modifications to enhance posttraining readiness.

This essay examines, in an evolutionary perspective, body systems outside the brain that use the catecholamines dopamine (DA), norepinephrine (NE), and epinephrine (EPI) as chemical messengers. Peripheral catecholamine systems represent three mechanisms by which the brain regulates the functions of body organs. DA serves as an autocrine-paracrine factor in the kidneys and splanchnic organs, NE is the neurotransmitter of the sympathetic noradrenergic system (SNS), and EPI is the main hormone secreted by adrenomedullary chromaffin cells. Comparative physiological data suggest that the DA autocrine-paracrine system emerged first, followed by noradrenergic nerve networks culminating in the SNS, with the hormonal sympathetic adrenergic system (SAS) appearing most recently. Examples are presented of the diverse ways these catecholamines have been used during evolution, although the ecological niches that conferred selective advantages remain uncertain. The discussion addresses catecholamine receptors, cotransmission, and interactions between catecholaminergic, neuroendocrine, and immune systems. In humans, the transition to bipedalism likely promoted SNS adaptations for orthostatic regulation of brain blood flow as well as for sodium homeostasis and temperature control. The roles of the SAS in organism-wide stress responses, distress, and sympathoadrenal imbalance in fainting are also considered. Concepts such as antagonistic pleiotropy, allostatic load, and autotoxicity are discussed in relation to aging-associated diseases that feature catecholaminergic neurodegeneration. Understanding the phylogeny of peripheral catecholamine systems may provide a foundation for Darwinian medicine.

A rapid change in arterial CO₂ tension causes changes in ventilation, referred to as peripheral hypercapnic chemosensitivity (PHC). The PHC increases from rest to low-intensity exercise yet is not further augmented at higher exercise intensities, where additional ventilatory stimulants are present. During supra-respiratory compensation point (RCP) exercise, as arterial CO₂ tension falls, so does PHC, which may mask the effect of other ventilatory stimuli. Twenty healthy subjects (n = 10 females) completed a maximal exercise test and on subsequent days (days 2 and 3) had PHC measured at rest, 40% of maximal work rate (Wmax), and supra-RCP exercise intensities. On one experimental day, participants were kept isocapnic, and on the other, end-tidal carbon dioxide ([Formula: see text]) declined naturally during supra-RCP exercise (poikilocapnia). PHC was measured as the quotient between the change in ventilation and [Formula: see text] after two breaths of hypercapnic (10% CO₂) gas delivered 3-5 times during each condition. There was a significant increase in PHC during supra-RCP intensities with isocapnia, compared with poikilocapnic exercise (+11.2 ± 6%) (P = 0.0015). Yet during the isocapnia day, there was still no significant increase in PHC from 40% intensity to supra-RCP (P = 0.96). A repeated-measures correlation demonstrated a significant relationship between PHC and [Formula: see text] during poikilocapnia (r = 0.49, P < 0.001), with no significant relationship during isocapnia (r = 0.06, P = 0.57). We conclude that the metabolic milieu associated with supra-RCP exercise does not impact PHC and there is a CO₂-dependent relationship in which [Formula: see text] influences PHC independent of the initial exercise sensitization.NEW & NOTEWORTHY Maintaining end-tidal carbon dioxide ([Formula: see text]) at isocapnic levels during supra-respiratory compensation point (RCP) exercise significantly increased the peripheral hypercapnic chemoresponse (PHC) compared with poikilocapnic conditions. However, neither the isocapnic nor poikilocapnic exercise above RCP resulted in a significant increase in PHC compared with lower intensity exercise. Thus, although prestimulus [Formula: see text] impacts the PHC, supra-RCP exercise does not further augment the PHC beyond low intensity exercise.