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

Environmental light-dark (LD) cycles serve as the primary zeitgeber for the mammalian circadian system, but scheduled physical activity such as voluntary wheel running can act as a potent nonphotic cue. Previous studies on nonphotic entrainment have predominantly used male animals, leaving sex-specific mechanisms largely unexplored. In this study, we investigated circadian behavioral entrainment and phase-shifting responses to scheduled wheel-running activity in female C57BL/6J mice under constant darkness (DD). Mice underwent scheduled daily exposure to a novel cage with a running wheel (NCRW) for 3 h, and spontaneous locomotor rhythms were analyzed before, during, and after exposure. Fifteen of 16 female mice achieved steady-state entrainment when the NCRW schedule coincided with activity onset. However, they lacked both anticipatory behavior and behavioral aftereffects of entrainment-defined as persistent changes in circadian period and activity timing following entrainment-unlike what has been previously reported in males. To interpret entrainment dynamics, we constructed phase response curve (PRC) for a single 3-h pulse of exposure to NCRW in both sexes. Female PRC displayed prominent delay portions in the late subjective day and early subjective night, contrasting with male profiles showing minor advances in the same windows. These findings reveal a sex difference in nonphotic circadian entrainment and suggest that underlying mechanisms, including oscillator coupling or differential sensitivity to nonphotic stimuli, may vary between males and females. The results emphasize the importance of considering biological sex in circadian research and provide a basis for further investigation into sex-specific regulation of behavioral rhythms.NEW & NOTEWORTHY This study reveals sex-specific differences in nonphotic circadian entrainment induced by scheduled wheel-running activity in mice. Female mice exhibited distinct phase response curves and lacked behavioral aftereffects, contrasting with previously reported male patterns. These findings highlight the importance of biological sex in circadian regulation and suggest that nonphotic entrainment mechanisms may differ fundamentally between sexes.

Whether cerebral pressure-flow relationship directional sensitivity, which represents the attenuated changes in cerebral blood velocity in response to transient increases, compared with decreases, in mean arterial pressure (MAP), is altered in lowlanders at high altitude or differs between lowlanders and Sherpa (a well-adapted highlander population of the Nepalese Khumbu region) is unknown. Both MAP and middle cerebral artery mean blood velocity (MCAv) were recorded continuously during 5-min repeated squat-stands (RSS) at 0.05 Hz and 0.10 Hz at sea level (n = 10), initial exposure to high-altitude (n = 8), after 2 wk of partial acclimatization to high-altitude (n = 9), and in Sherpa (n = 16). For each transition, we calculated absolute and relative MCAv and MAP changes with respect to the transition time intervals of both variables indexing time adjusted ratios when MAP increases (ΔMCAv_T/ΔMAP_T^INCREASE and %MCAv_T/%MAP_T^INCREASE) and decreases (ΔMCAv_T/ΔMAP_T^DECREASE and %MCAv_T/%MAP_T^DECREASE). Regardless of altitude conditions, %MCAv_T/%MAP_T^INCREASE was lower than %MCAv_T/%MAP_T^DECREASE [0.05 Hz RSS: (P = 0.007); 0.10 Hz RSS (P = 0.003)] in lowlanders. Partially acclimatized lowlanders and Sherpa had lower %MCAv_T/%MAP_T^INCREASE than %MCAv_T/%MAP_T^DECREASE at 0.05 Hz (P = 0.007), but comparable metrics at 0.10 Hz RSS (P = 0.971). These findings indicate acute exposure and partial acclimatization to high altitude do not alter the cerebral pressure-flow relationship directional sensitivity compared with sea level measures in lowlanders. In addition, the hysteresis-like pattern in Sherpa is not different when compared with partially acclimatized lowlanders.NEW & NOTEWORTHY Cerebral blood flow changes are buffered when blood pressure increases versus decreases. The current findings suggest that acute exposure and partial acclimatization to high altitude do not influence the presence of this phenomenon in lowlanders. Preservation of this hysteresis-like pattern across all altitude conditions may protect the cerebral microvasculature from hypoxia-induced increases in blood pressure. However, cerebral pressure-flow directional sensitivity is absent in Sherpa, a well-adapted highlander population, when blood pressure oscillates at higher frequency.

The core temperature inflection point (CTIP) method (also known as humidity-ramp protocol) and biophysical modeling are widely used to determine human thermoregulation limits, yet their validity under prolonged heat exposure remains unverified. This study evaluated the predictive accuracy by exposing 36 healthy young adults (20 males and 16 females) to five counterbalanced 8-h indoor heat trials in a controlled chamber (36°C/74.5%RH, 40°C/55.0%RH, 44°C/29.2%RH, 47°C/35.6%RH, and 50°C/24.5%RH). These conditions were selected based on prior CTIP and biophysical model predictions of human thermoregulation limits. Participants engaged in sedentary office tasks (1.29-1.67 METs), wore standardized summer clothing (0.39-0.40 clo), and had ad libitum access to an electrolyte drink, with a 500-kcal sandwich provided at midday. Rectal temperature (T_rec) was continuously monitored. Contrary to model predictions, all five conditions remained compensable (T_rec rise rate ≤ 0.1°C/h), with mean peak T_rec well below heatstroke thresholds (38.2 ± 0.4°C). At 44°C/29.2%RH, females exhibited significantly lower T_rec than males (P < 0.05); however, no sex differences in steady-state T_rec responses were observed across other conditions (all P > 0.10). All exposures were compensable, aligning with the broader literature indicating minimal sex-based variability under such conditions. Collectively, CTIP and biophysical models substantially underestimated human thermoregulation limits, leading to overpredicted heat risk across all trials. These findings challenge the reliability of current predictive methods, suggesting human tolerance may exceed existing estimates. Refining these models is essential for improving heat risk assessment and informing public and occupational health guidelines in a warming climate.NEW & NOTEWORTHY This study reveals that widely used methods-core temperature inflection point and biophysical models-substantially underestimate human thermoregulation limits during prolonged heat exposure. Despite predictions of uncompensable heat stress, all five 8-h trials remained compensable, with core temperatures well below critical thresholds. These findings challenge the accuracy of current predictive tools and highlight the need to refine models to better assess heat risk in real-world, prolonged exposure scenarios.

Calorie restriction (CR) is a well-established weight loss strategy, albeit with variation in response. Using genetically heterogeneous mice, we sought to identify metabolic predictors of resistance to CR-induced weight loss. Diversity outbred (DO) mice (150 males and 150 females) were fed a high-fat diet for 12 wk to generate diet-induced obesity (DIO), then underwent CR for 8 wk. Body weight and composition, blood glucose, and plasma levels of nine metabolic hormones were assessed at baseline, following DIO, and following CR. In response to each dietary intervention, the mice displayed substantial heterogeneity across all outcomes, often with sexual dimorphism. Among the metabolic markers, leptin changed the most in response to each dietary intervention. Logistic regression found that resistance to CR-induced weight loss in obese mice was associated with lower glucose levels in males, and with lower levels of insulin, resistin, homeostatic model assessment for insulin resistance (HOMA-IR), and plasminogen activator inhibitor-1 and higher levels of ghrelin in females. Moreover, lower leptin levels predicted resistance to CR-induced weight loss in obese mice, regardless of sex. These preclinical findings provide proof-of-principle that the genetic and phenotypic heterogeneity of DO mice can be leveraged to identify mechanistic predictors that may enhance the personalization of weight loss interventions.NEW & NOTEWORTHY Using a population of obese diversity outbred (DO) mice, we interrogated plasma predictors of resistance to calorie restriction-induced weight loss in nonresponders versus responders to the diet intervention. Lower leptin levels significantly predicted resistance in both sexes. Sexually dimorphic predictors included lower levels of glucose in males and insulin, resistin, and plasminogen activator inhibitor-1 (PAI-1) in females. Hence, genetically and phenotypically heterogeneous diversity outbred mice may be useful for identifying metabolic predictors for personalizing weight loss interventions.

Aging is associated with a progressive increase in risk and prevalence of cardiovascular disease (CVD). Circulating extracellular vesicles, particularly endothelial cell-derived microvesicles (EMVs), have been linked to the development and progression of endothelial dysfunction and CVD. The purpose of this study was to determine 1) if circulating EMV levels increase with age, independent of other cardiometabolic risk factors; and if so, 2) whether circulating EMVs are associated with age-related endothelial vasodilator dysfunction. Forty healthy, nonobese, normotensive, sedentary males were studied: 12 young (age: 27 ± 5 yr), 14 midlife (51 ± 5 yr), and 14 older (67 ± 5 yr). EMV identification (CD31⁺/42b^-) and concentration in peripheral blood were determined by flow cytometry. Forearm blood flow (FBF: via plethysmography) was assessed in response to intra-arterial infusions of acetylcholine and sodium nitroprusside. Circulating EMV levels were significantly and progressively higher across the young, midlife, and older groups (54 ± 14 vs. 101 ± 30 vs. 132 ± 54 EMV/µL, respectively). FBF response to acetylcholine was significantly lower (∼30%) in the midlife (4.5 ± 0.8 to 13.5 ± 3.3 mL/100 mL tissue/min) and older (4.2 ± 1.0 to 11.5 ± 2.8 mL/100 mL tissue/min) vs. young (from 5.2 ± 1.1 to 17.2 ± 4.9 mL/100 mL tissue/min) group. Circulating EMVs were positively associated with age (r = 0.69; P < 0.001) and inversely associated with endothelial vasodilation (peak FBF to acetylcholine: r = -0.51; and total FBF to acetylcholine: r = -0.48; P = 0.02). Aging, independent of other cardiometabolic risk factors, is associated with progressively elevated circulating levels of EMVs in healthy males. Circulating EMVs may serve as a biomarker of, and potential contributor to, age-related endothelial dysfunction and vascular disease risk.NEW & NOTEWORTHY Aging is associated with progressive decline in endothelium-dependent vasodilation. Mechanisms underlying this decline in endothelial function are not fully understood. Circulating endothelial cell-derived extracellular vesicles (EMVs) have been linked to endothelial dysfunction. The results of the study demonstrate that circulating EMVs increase with age in healthy males and are associated with endothelial vasodilator dysfunction. Circulating EMVs represent a novel systemic biomarker, and potential mediator, of age-related decline in endothelium-dependent vasodilation.

The objective of this study was to explore sex and heating rate effects on frequency-domain indicators of the mechanisms modulating cutaneous vasodilation during local heating. In 30 young adults (21 ± 3 yr, 15 females), wavelet analysis of skin blood flux was assessed from laser-Doppler flux signals at the chest, abdomen, arm, forearm, thigh, and calf during rapid (33-42°C; 1°C·20 s^-1) and gradual (33-42°C; 1°C·5 min^-1) local skin heating. A wavelet transform using a Morlet mother wavelet was computed over the entire signal for each heating protocol (minimum 90 min), and 5-min time windows were subsequently isolated to determine responses during baseline and the 42°C heating plateau. Wavelet data were decomposed into metabolic, neurogenic, myogenic, respiratory, and cardiac frequency bands and presented as absolute and relative (normalized) amplitudes. There was a significant sex by heating rate interaction for relative wavelet amplitude in the metabolic frequency band (P = 0.003), which was 0.89-fold [0.82, 0.98] lower (P = 0.006) during rapid heating compared with gradual heating for females only. There were no significant interactions for the other frequency bands (all P ≥ 0.054). Males showed greater absolute and relative amplitudes for neurogenic and myogenic bands compared with females (all P ≤ 0.022). Rapid heating resulted in significantly lower absolute amplitudes for metabolic, neurogenic, and cardiac bands compared with gradual heating (all P ≤ 0.004). However, there was a significantly greater relative amplitude for the respiratory band during rapid heating compared with gradual (P = 0.030). These exploratory findings highlight important sex and heating rate effects on wavelet-based indicators of the mechanisms modulating cutaneous vasodilation during local heating.NEW & NOTEWORTHY Wavelet analysis showed males relied more on neurogenic and myogenic mechanisms than females to modulate skin blood flow during local heating. Rapid heating produced lower absolute wavelet amplitudes for metabolic, neurogenic, and cardiac frequency bands compared with gradual heating. Frequency-domain responses showed weak discrimination between skin sites across the torso and limbs. Our findings highlight sex and heating rate effects on cutaneous vasodilator mechanisms during local heating using noninvasive wavelet-based approaches for understanding microvascular control.

With rising average global temperatures, extreme heat events are becoming more frequent and intense, placing heat-vulnerable older adults at an elevated risk of mortality and morbidity. We recently showed that a brief 2 h access to air-conditioning during a simulated heatwave confers cytoprotective benefits in older adults; however, air-conditioning is inaccessible to many. Although foot immersion and neck cooling have been proposed as alternative cooling strategies, their effects on cellular stress are unclear. We evaluated cellular responses (autophagy, apoptosis, acute inflammation, and heat shock proteins) in peripheral blood mononuclear cells from 17 participants (9 females, median age: 72 [IQR, 69-74] yr) who completed three, 6-h heat exposures at 38°C (35% relative humidity) with either no-cooling (control), submersion of the feet (mid-calf) in 20°C water for 40-min each hour or foot immersion with a cool wet towel (20°C) around the neck. Core (rectal) temperature was measured continuously. Western blot analysis was used to assess changes in protein responses at baseline and end exposure. Despite similar elevations in core temperature between conditions, p62 concentrations were elevated in the control compared with both foot immersion with [mean difference: 0.4 relative quantity (RQ); P = 0.046] and without (0.6 RQ; P = 0.026) neck cooling. Furthermore, HSP70 concentrations were elevated in control compared with foot immersion (0.7 RQ; P = 0.030). No changes between conditions were observed for apoptotic or inflammatory proteins. Although foot immersion with or without neck cooling had minimal impact on core temperature, these strategies may improve autophagic responses in older adults when exposed to extreme heat.NEW & NOTEWORTHY As the incidence and severity of heatwaves continue to rise, there is an urgent need to develop accessible and sustainable heat-alleviation strategies. We evaluated the use of foot immersion in cool water with or without the addition of a damp towel around the neck on cellular stress responses in older adults exposed to extreme heat. Although neither cooling intervention reduced elevations in core temperature, both cooling strategies may improve autophagic responses in older adults.

We propose the interfacial water quantum-transition (IWQ) model as a novel paradigm explaining temperature-dependent structural and functional transitions (discontinuities) observed in proteins. The central postulate states that experimentally measured critical temperatures, T_C, are related to physical reference temperatures, T_W, defined by rotational quantum transitions of temporarily free water molecules in the protein-water interface. Applicability of this concept is demonstrated with transitions observed in two disparate model systems, viz., hemoglobin and thermosensitive transient receptor potential (TRP) channels. We propose that the same mechanism underlies the definition of basal body temperatures in homeotherms, the reference temperature for humans being T_W = 36.32°C. Specifically, we demonstrate that the body temperatures of both human and chicken (representing the two classes of homeothermic vertebrates) not only coincide with quantum-transition reference temperatures but are also related to pronounced transitions in hemoglobin oxygen saturation. This suggests that the evolution of body temperatures in different homeothermic species might involve an interplay between critical parameters of oxygen supply on the one hand and quantum-physical rotational transition temperatures of water on the other. Casting the IWQ model concept into a concise formula: Proteins sense and water sets critical physiological temperatures.NEW & NOTEWORTHY We propose the interfacial water quantum-transition (IWQ) model to explain how proteins respond to temperature changes through specific quantum transitions of water at the protein-water interface. This model links key functional temperatures, such as human body temperature, to these transitions. By examining proteins like hemoglobin and thermosensitive channels, the IWQ model reveals a fundamental connection between water behavior and biological temperature regulation, shedding light on evolutionary adaptations in humans and animals.