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

Exposure to an elevated state of hyperthermia is associated with heat-induced cytotoxicity, which, if left unabated, can cause tissue damage and death. Although activation of autophagy is vital to counter heat-induced cellular injury and promote cellular survival, the dose-dependent autophagic response to controlled elevations in body core temperature has yet to be evaluated in an in vivo human model. Therefore, on separate days, we evaluated cellular responses in 12 young adults [means (SD): 22 (2) yr; 6 women] who were immersed (up to the clavicle) in water set at a temperature to clamp core temperature (esophageal) at either baseline resting (control; 37°C), warm (38°C), or hot (39°C) conditions for 60 min. Autophagy was characterized in peripheral blood mononuclear cells before and after water immersion, as well as following 3 h of seated recovery in a temperate environment (∼22°C). Proteins associated with autophagy and cellular stress pathways (apoptosis, inflammation, and heat shock response) were assessed via Western blot. With increasing levels of hyperthermia, we observed increasing autophagic activation (as indexed via elevated LC3-II and decreasing p62) at end exposure to warm and hot core temperature clamps, with evidence of elevated autophagic activity up to 3 h after exposure to the hot condition. This was paired with significant end exposure elevations in cellular stress proteins including cleaved-caspase-3, TNF-α, and IL-6 in the hottest condition. Taken together, our findings suggest that autophagy is activated with increasing levels of hyperthermia and may be important in restoring cellular homeostasis when exposed to body core temperatures above 38°C in healthy young adults.NEW & NOTEWORTHY Our findings suggest that autophagic regulation is stimulated in peripheral blood mononuclear cells associated with elevations in body core temperature induced through warm-to-hot water immersion. Importantly, our findings propose that autophagy may be important in restoring cellular homeostasis when exposed to body core temperatures above 38°C in healthy young adults. Therefore, the use of warm-to-hot water immersion may provide a potent model to study cellular heat stress responses in humans.

The morphology of the larynx is essential for vocalization, respiration, and airway protection, yet the sources of phenotypic variation within species are not well understood. This study investigated whether genetic background exerts a stronger influence than environmental factors on laryngeal morphology in two house mouse strains. Using geometric morphometrics, we analyzed the size and shape of 79 laryngeal specimens and examined the effects of body size, genetics, obesity, exercise, and social housing. Our results demonstrate that genetic background significantly shapes laryngeal structure. There were significant shape differences between the two genetic strains, and the inbred strain showed less phenotypic variation than the outbred mice. Although these structural differences likely arose without direct selection, they were associated with marginal differences in vocal output, suggesting functional relevance. Obesity and exercise also influenced laryngeal morphology, but their effects were secondary to genetics. Notably, leptin levels were linked to size and shape changes in the vocal organ. These findings suggest that random genetic drift and pleiotropy can be important drivers of laryngeal evolution in house mice. Overall, both genetic and environmental factors contribute to laryngeal shape, underscoring the organ's plasticity.NEW & NOTEWORTHY How are voice, swallowing, and breathing shaped by genes, environment, and diet? This study in house mice shows that genetic background, obesity, exercise, and social housing all influence laryngeal structure and function. Laryngeal shape seems to be affected by pleiotropy and genetic drift. Outbred mice show greater variation than inbred ones, and leptin-deficient mice have smaller vocal organs-highlighting the larynx as a dynamic, responsive structure shaped by multiple forces.

Major depressive disorder (MDD) often first emerges during young adulthood and is associated with an increased risk of future hypertension, but our understanding of blood pressure (BP) regulation in young adults with MDD who are otherwise clinically healthy remains limited. We tested the hypothesis that beat-to-beat BP variability (BPV) would be greater in young unmedicated adults with MDD compared with nondepressed healthy adults (HA). Because the arterial baroreflex is essential for beat-to-beat BP regulation, we also hypothesized that 1) sympathetic baroreflex sensitivity would be reduced in young adults with MDD and 2) positively related to BPV. Beat-to-beat BP (finger photoplethysmography), heart rate (ECG), and muscle sympathetic nerve activity (MSNA; peroneal microneurography) were measured during 10-20 min of supine rest in 40 young adults with MDD (unmedicated; n = 19 females) and 27 HA (n = 17 females). There were no group differences in either resting BP (116 ± 10/73 ± 6 HA vs. 113 ± 9/74 ± 6 mmHg MDD; both P > 0.05) or MSNA (26 ± 11 vs. 24 ± 13 bursts/100 heartbeats MDD; P = 0.50). Neither beat-to-beat BPV (e.g., systolic BP standard deviation: 5.8 ± 2.1 HA vs. 5.9 ± 1.6 mmHg MDD, P = 0.47) nor sympathetic baroreflex sensitivity (e.g., burst incidence gain: -3.8 ± 1.3 HA vs. -3.4 ± 1.5 bursts/100 beats/mmHg MDD, P = 0.34) was different in MDD compared to HA. In adults with MDD, sympathetic baroreflex sensitivity was related to BPV (r = 0.52, P = 0.01). Traditional measures of beat-to-beat cardiac output and total peripheral resistance variability were likewise not different between groups (all P > 0.05). These data demonstrate that both beat-to-beat BPV and sympathetic baroreflex sensitivity are preserved in young unmedicated adults suffering from MDD.NEW & NOTEWORTHY This study investigated beat-to-beat blood pressure variability (BPV) in young unmedicated adults with major depressive disorder (MDD). The results demonstrated that both BPV and sympathetic baroreflex sensitivity were preserved in young unmedicated adults with MDD compared with healthy nondepressed young adults.

Strenuous physical work in hot environments can impair kidney function and potentially cause acute kidney injury (AKI). Heat acclimation is recommended to reduce thermal strain but its efficacy in mitigating decrements in kidney function remains unclear. The present study tested the hypothesis that 10 days of heat acclimation attenuates increases in serum creatinine (ΔCr) during exercise heat stress. Twenty healthy adults (14 females) completed 10 days of fixed-intensity treadmill walking for 120 min in a climatic chamber (40°C) to induce heat acclimation. Kidney function was assessed as ΔCr from pre-to-post exercise on days 1 (D1) and 10 (D10). Plasma neutrophil gelatinase-associated lipocalin (ΔNGAL) was measured to estimate the magnitude of renal ischemia. The increase in core temperature (Tc) from pre- to postexercise was attenuated on D10 (Post: 38.3 ± 0.4°C) compared with D1 (Post: 38.8 ± 0.5°C, P < 0.001). Heat acclimation did not alter the increase in ΔCr and ΔNGAL to exercise heat stress (P ≥ 0.325). There was a strong correlation between ΔTc and ΔCr on D10 (r = 0.61) but no correlation on D1 (P = 0.908). There was no correlation between ΔTc and ΔNGAL on either day (P ≥ 0.480). There was a strong correlation between ΔNGAL and ΔCr on D1 (r = 0.694) but no correlation on D10 (P = 0.118). These findings indicate that heat acclimation does not alter the magnitude of increase in circulating biomarkers of kidney function following exercise heat stress. However, that ΔCr was correlated with ΔTc on D10 but not on D1 suggests that the kidneys may exhibit increased sensitivity to hyperthermia in heat-acclimated individuals.NEW & NOTEWORTHY Heat acclimation provides beneficial adaptation during heat stress. The impact of heat acclimation on kidney function are not well understood. This short report provides findings that plasma neutrophil gelatinase-associated lipocalin (NGAL) and creatinine appear to be unaffected by acute heat stress before and after heat acclimation, but that the kidneys may exhibit increased sensitivity to hyperthermia in heat-acclimated individuals.

Exercise during heat exposure induces skin microvascular and systemic cardiovascular changes. When standardized exercise tasks are completed, such as during military training or in workplace settings, sex differences in responses may be apparent. Nineteen males and 19 females participated in a set-pace laboratory walking test (treadmill walking 5 km/h; 2% incline) in a climate chamber (40°C; 50% RH) for 90 min. Body composition (DXA) and aerobic capacity (V̇o_2max) were measured in a preliminary session. Metabolic heat production, skin blood flow (SkBF; laser Doppler flowmetry), limb blood flow (Doppler ultrasound), stroke volume, cardiac output (CO), heart rate (HR), oxygen consumption (V̇o₂), and core temperature (Tc) were measured at baseline, 30, 60, and 90 min. No sex difference in Tc at 90 min was evident (male 38.3 ± 0.5°C vs. female 38.5 ± 0.4°C; P = 0.403) and a similar change from baseline to 90 min (Δ 1.40 vs. 1.28°C; P = 0.447) occurred, despite males producing more heat (3.4 ± 1.0 vs. 2.1 ± 0.7 W/kg; P = 0.001), exhibiting higher SkBF (192 ± 50 vs. 160 ± 21 PU; P = 0.026), and higher sweat production rate (16.5 ± 5.1 vs. 12.3 ± 3.3 mL/min; P = 0.009). Males also had higher CO (7.25 ± 1.38 vs. 6.11 ± 1.72 L/min; group P = 0.026) and femoral blood flow (1.00 ± 0.23 vs. 8.22 ± 0.19 L/min; P = 0.026) responses than females. Males compensated for more lean mass and higher metabolic heat production via a larger increase in cardiac output, with more blood flow distributed to active muscle and, as heat and exercise exposure continued, to the skin. Tc in females did not rise more than in males, possibly due to body size and/or anthropometric factors.NEW & NOTEWORTHY In military, workplace, and sporting settings, challenging environmental conditions while performing external workloads are not always avoidable. We assessed sex differences during a 90-min treadmill walk (40°C). Males produced more metabolic heat, had higher skin blood flow, sweat rate, and cardiac output than females. Change in core temperature remained similar between sexes, challenging the proposition that women are more heat-intolerant than men. Our findings underscore the need for tailored heat tolerance strategies for both sexes.

Preeclampsia, new-onset hypertension with proteinuria or end-organ dysfunction after 20 wk gestation, is associated with placental ischemia, maternal endothelial dysfunction, and chronic inflammation. Preeclamptic women and the reduced uterine perfusion pressure (RUPP) rat model of placental ischemia have higher placental expression and activation of NLRP3 inflammasome and its associated cytokine, interleukin 1β (IL-1β). We hypothesized that higher IL-1β signaling through the IL-1 receptor type 1 (IL-1R1), contributes to maternal hypertension, fetal growth restriction (FGR), and endothelial dysfunction in response to placental ischemia. GD14 timed-pregnant Sprague-Dawley rats underwent RUPP or sham surgery with implantation of minipumps infusing IgG or IL-1R1 neutralizing antibody (αIL-1R1; 2 μg/kg/day). On GD19, mean arterial pressure (MAP), fetal and placental weights, blood, and tissues were collected. Plasma IL-1β was higher in RUPP vs. Sham IgG controls (8.79 ± 2.01 vs. 3.24 ± 1.05 pg/mL; P < 0.01) and normalized in RUPP + αIL-1R1 (1.23 ± 0.51 pg/mL; P < 0.01 vs. RUPP + IgG). MAP was higher at 120 ± 4 mmHg in RUPP + IgG from 100 ± 3 mmHg in Sham + IgG (P < 0.01). αIL-R1 treatment reduced MAP to 106 ± 12 mmHg in RUPP (P < 0.01 vs. RUPP + IgG). RUPP + IgG placenta weight (0.46 ± 0.1 g) was lower than Sham + IgG (0.54 ± 0.1 g; P < 0.01) and significantly higher in RUPP + αIL-R1 (0.52 ± 0.02 g; P < 0.05 vs. RUPP + IgG). Fetal weight was higher in RUPP + αIL-1R1 (2.77 ± 0.22 g) vs. control RUPP (1.97 ± 0.11 g; P < 0.01). Placental cNK, T_H17s, and macrophages were higher, and T_Regs were lower in RUPP + IgG vs. Sham, and were normalized in RUPP + αIL-1R1 (P < 0.05). IL-1R1 inhibition decreased IL-1R1 expression but did not reverse RUPP-induced changes in NFκB, preproendothelin, or endothelial nitric oxide synthase expression. IL-R1 activation contributes to maternal hypertension and FGR via mediating immune populations during ischemia.NEW & NOTEWORTHY IL-1R1 inhibition in the reduced uterine perfusion pressure (RUPP) rat model of preeclampsia lowered maternal blood pressure, reduced fetal reabsorptions, and improved fetal and placental growth. These effects were accompanied by restored systemic and placental immune balance but no improvement in vascular markers such as VEGF or preproendothelin. Thus, IL-1R1 blockade, including the clinical agent anakinra, is a promising therapeutic avenue that may require combination strategies for optimal benefit.

The goal of this study was to determine which phase of swallowing causes deglutitive inhibition (DI). DI is inhibition of ongoing peristalsis by a new swallow. Pharynx and esophagus of decerebrate cats (n = 25) were instrumented to record esophageal peristalsis. Injecting saline into pharynx or esophagus activated primary (pharyngeal and esophageal phases) peristalsis repeatedly and randomly, or secondary (esophageal phase) peristalsis once, respectively. When a new primary peristalsis occurred during ongoing primary peristalsis, the occurrence of ongoing esophageal peristalsis was blocked when it was 1-10 cm from upper esophageal sphincter, then secondary peristalsis occurred 1.3 ± 0.1 s (n = 22) later at same location. This esophageal blockade occurred almost simultaneously [0.15 ± 0.01 s (n = 17) before] with activation of thyropharyngeus activation during the new pharyngeal phase. When ongoing primary peristalsis was at or below 13 cm from upper esophageal sphincter, the magnitude of primary esophageal peristalsis significantly decreased (102 ± 14 vs. 49 ± 8 mm Hg, n = 8, P < 0.01) during the new pharyngeal phase, but peristaltic progression was not altered. DI had same effects on secondary peristalsis. DI of ongoing peristalsis in distal esophagus occurred before or without new esophageal phase in every case (21 cases, n = 9), except one. DI is central inhibition of ongoing esophageal phase of swallowing by the new pharyngeal phase as short-term cessation of striated muscle peristalsis and longer-term reduction in smooth muscle peristaltic magnitude. Esophageal or oral phase of swallowing does not cause DI.NEW & NOTEWORTHY Deglutitive inhibition is caused by central inhibition of ongoing esophageal phase of swallowing during the new pharyngeal phase by short-term cessation of striated muscle peristalsis and longer-term reduction in smooth muscle peristaltic magnitude. The esophageal or oral phase of swallowing does not cause deglutitive inhibition. Deglutitive inhibition is pharyngeal phase central inhibition of the esophageal phase of swallowing.

Findings of falling urine pH with age among stone formers have not been explained by changes in renal function or renal ammonia production with age. We collected and analyzed 245 urine samples from 190 stone-forming subjects (95 male) and 55 normal subjects (18 male) to expand on our previous study using urine titration to explore whether urine organic anion (Uoa) contributes to acid load and rises with age. We stratified our previous titration protocol to include three pKa subranges, 2.70-3.60, 3.61-4.30, and 4.31-7.40, to measure effects of Uoa of differing pKa values on renal acid excretion. We found that Uoa behaves as a metabolic acid, and associates independently and positively with ammonia (P < 0.001). Uoa in pKa range 2.70-3.60 is the principal acid component and rises with age (P < 0.001), whereas Uoa in pKa range 4.31-7.40 seems to reflect net alkali excretion when studied in a regression model with the kidney as a reporter organ. When factored per urine creatinine, we found significant age and sex effects of nearly all components of renal acid-base balance. Effects from subject type (stone former vs. normal) were minimal, though we are limited by the oldest tertile having few normals. As acid anions with pKa within 2.70-3.60 are used in the tricarboxylic acid cycle, markers of acid excretion may reflect mitochondrial abnormalities associated with aging.NEW & NOTEWORTHY When assessed using the kidney as a reporter organ, titrated urine anions behave overall as an acid load. However, those in the pKa range of 2.70-3.60 account for much of that behavior, whereas anions in the pKa ranges above 3.60 variably behave as alkali or acid, indicating that the urinary anions are heterogeneous. Despite their differences in function, they all rise with age. This may explain acid stress reported as part of the aging phenotype.

Accurate and reproducible tools to evaluate skeletal muscle contractility help to advance the field of physiology by defining skeletal muscle function in the context of skeletal muscle development, disease, aging, and injury recovery. The biomechanical assessment of muscle strength can be accomplished by measuring in vivo muscle torque, specifically, the muscle force generated at a moment arm around a joint. This approach to assess skeletal muscle contractility in preclinical animal studies primarily measures muscle torque in anesthetized animals using noninvasive electrophysiological stimulation. This method is advantageous because skeletal muscle contractions are evoked in a controlled, quantifiable manner that is independent of subject motivation, allowing for maximal functional data and reproducible research outcomes. The purpose of this Cores of Reproducibility in Physiology (CORP) review is to discuss the underlying physiology of the in vivo method, to highlight common outcomes and their physiological importance, and to provide considerations for technical reproducibility and data interpretation. The hope is this CORP will provide skeletal muscle researchers with the foundational and practical knowledge to better incorporate the in vivo technique in their future studies.

Dynamic cerebral autoregulation (dCA) demonstrates directional sensitivity (DS_CA), depending on increases or reductions in mean arterial blood pressure (MAP). DS_CA dependence on the efficiency of dCA has not been reported. A retrospective study of 172 healthy subjects (88 female, age 19-82 yr), with 5-min recordings of MAP, cerebral blood velocity (middle cerebral artery, MCAv), end-tidal CO₂, and electrocardiogram, led to estimates of the MCAv step response to changes in MAP. The strength of DS_CA was expressed by the difference between the MCAv step responses for the positive derivative component of MAP and the corresponding negative derivative component. The efficiency of dCA was expressed by the original autoregulation index (ARI_orig), ranging from 0 to 9, calculated from the original MAP. For the entire population, DS_CA strength was not associated with ARI_orig or any other parameters. However, when taking biological sex and age into account, markers of DS_CA strength showed significant linear regressions with ARI_orig, with negative slopes for younger females (P = 0.0037-0.011, late phase of the step responses), no influence in older females (P > 0.69), and positive slopes for both younger and older males (early phase of the step responses, P = 0.003-0.041). This contrasting pattern of the influences of sex and age is in agreement with the known effects of gonadal hormones on the myogenic response and endothelial function of the cerebral circulation. Clinical studies of the diagnostic and/or prognostic value of DS_CA parameters need to take into account the influences of sex, age, and the ARI_orig.NEW & NOTEWORTHY Dynamic cerebral autoregulation (dCA) is more efficient for increases in mean arterial blood pressure (MAP) compared with reductions in MAP. We found that directional sensitivity of dCA is dependent on its efficiency, with differences depending on sex and age. In older women, strength of directional sensitivity (DS_CA) is not affected by dCA efficiency, but in younger women, DS_CA decreases with dCA efficiency, whereas in both younger and older men, DS_CA strength increases with dCA efficiency.