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

Endothelial monocyte-activating polypeptide II (EMAP-II) is a pro-inflammatory cytokine that has been recently shown to be involved in the cellular heat stress response following prolonged work in the heat. However, its response during prolonged passive heat exposure, such as during extreme heat events, or how chronic disease and ageing modify this response, is not well characterised. We assessed serum EMAP-II concentrations at baseline and at the end of 9 hours of passive heat exposure (end-exposure) (40°C, 9% relative humidity) in 19 young adults (21-27 years) and 37 older adults (68-73 years), including subgroups with hypertension (HTN) and/or type 2 diabetes (T2D). EMAP-II concentrations were significantly higher at end-exposure in young adults compared to older adults without HTN or T2D (mean difference [95% confidence interval]: 1.9[0.8, 3.0] pg/mL; p<0.014), with a greater relative increase from baseline (p=0.017). EMAP-II concentrations were significantly elevated at baseline in older adults with HTN (4.7[3.3, 6.1] pg/mL; p<0.001) and T2D (5.6[4.2, 7.0] pg/mL; p<0.001) compared with older adults without HTN or T2D. These elevations persisted at end-exposure in both the older adults with HTN (5.6[4.2, 7.0] pg/mL; p<0.001) and T2D (5.4[4.3, 6.4] pg/mL; p<0.001). Prolonged passive heat exposure elicited a significant EMAP-II response in young adults, indicating a more robust cytokine reactivity. In older adults without HTN or T2D, the response was attenuated, potentially reflecting age-related reductions in cellular stress signalling. In contrast, older adults with HTN and T2D showed significant responses, suggesting chronic disease may heighten inflammatory sensitivity to extreme heat.

We recently reported that countdown (CD) before voluntary exercise induced cerebral activation and pressor responses, resulting in muscle vasodilation (J Appl Physiol 128: 1196-1206, 2020). We examined whether responses were enhanced as peak aerobic capacity (⩒O_2peak) increased. We studied 27 young men with ⩒O_2peak from 25.2 to 61.4 ml·kg^-1·min^-1. We evaluated CD responses before initiating voluntary cycling at 50% of ⩒O_2peak for 1 min in a semi-recumbent position while measuring middle cerebral artery blood flow velocity (V_MCA; Doppler ultrasonography), heart rate, mean arterial pressure (MAP; finger photoplethysmography), oxygen consumption rate (⩒O₂), cardiac output (Q˙_c; Modelflow), total peripheral resistance (MAP/Q˙_c) and oxygen saturation in thigh muscle (near-infrared spectrometry). All subjects performed 8 trials, intermitted by ≥5-min rest, and were either given a 30-sec countdown (CD+) or immediately signaled to begin exercise (CD-), with the order randomized and counterbalanced. We classified subjects with both V_MCA and MAP increases by CD as "responders" (Resp, n=11) and those with either V_MCA or MAP increase, or an increase of neither, as "minimal responders" (MinResp, n=16). We found cerebro-cardiovascular and ⩒O₂ responses to CD before starting exercise were all significantly greater in Resp than MinResp (all, P<0.017), and cerebro-cardiovascular responses were significantly correlated with individual ⩒O_2peak in data pooled from both groups (all, P<0.034). The increase in ⩒O₂ by CD in Resp continued for a few seconds after starting exercise. Thus, cerebro-cardiovascular responses to CD before starting voluntary exercise were enhanced as individual ⩒O_2peak increased in young men, which might accelerate ⩒O₂ response at starting exercise.

Early-life infections have enduring effects on the immune and endocrine systems. Glucocorticoids (GCs) are produced by the adrenal glands and also produced by lymphoid organs (immunosteroids). We investigated the impacts of early-life lipopolysaccharide (LPS) challenge on GC and mineralocorticoid regulation in blood and lymphoid organs. We administered saline vehicle (nVEH) or LPS (50 μg/kg bw, ip) (nLPS) to neonatal mice on post-natal day (PND) 4 and 6 ("first hit"). We then administered saline vehicle (aVEH) or LPS (50 μg/kg bw, ip) (aLPS) to adults on PND90 ("second hit"), in a 2×2 design. We collected whole blood, bone marrow, thymus, and spleen 4 hr after treatment at PND90. We measured 9 steroids via liquid chromatography-tandem mass spectrometry and measured transcripts of steroidogenic enzymes (Cyp11b1, Cyp11b2, Hsd11b1, Hsd11b2), GC receptor, mineralocorticoid receptor, and HPA axis components (Crh, Crhr1, Pomc, Mc2r) via RT-qPCR. The nLPS treatment did not have significant effects on blood GC levels in adulthood. Nonetheless, nLPS treatment increased corticosterone and 11-dehydrocorticosterone levels in lymphoid organs of aLPS subjects. The nLPS treatment increased aldosterone levels in blood and bone marrow of aVEH females but decreased aldosterone levels in bone marrow and thymus of aVEH males. The nLPS treatment also increased transcripts for steroidogenic enzymes, especially the aldosterone-synthetic enzyme Cyp11b2, and modulated transcripts for steroid receptors, especially MR, in lymphoid organs of aVEH and aLPS subjects. These findings suggest that elevated local GC and aldosterone production in lymphoid organs is a mechanism for the enduring effects of early-life infections on immune function.

Exercise-induced fatigue is regulated by central nervous system (CNS)-derived factors, including neurotransmitters and metabolic signals, however, the underlying mechanisms remain incompletely understood. This study aimed to test whether lactate activates GPR81 in the motor cortex to inhibit PKA phosphorylation, thereby contributing to central fatigue during exercise. Using a murine weight-loaded swimming model, we found that PKA phosphorylation in the motor cortex increased significantly after 15 min of swimming, but decreased markedly after swimming to exhaustion. Notably, inhibition of PKA phosphorylation by local administration of H-89 in the motor cortex shortened the swimming time of mice (H-89 20 ± 5 min vs. saline 38 ± 6 min, p<0.05). Additionally, we found that activation of the lactate receptor GPR81 by local administration of CHBA or l-lactate attenuated exercise-induced upregulation of PKA phosphorylation. Conversely, genetic ablation of GPR81 (GPR81^-/-) mitigated the inhibitory effect of lactate on PKA phosphorylation, resulting in a 33% increase in swimming endurance. Despite comparable peripheral fatigue markers (blood lactate, skeletal muscle glycogen, and gastrocnemius pAMPK/AMPK ratio) after 30 minutes of swimming, GPR81^-/- mice exhibited elevated motor cortical glutamate/GABA ratios, indicating preserved neuronal excitability. Therefore, our study reveals a vital role of the lactate-GPR81 signaling axis in the motor cortex during exercise and provides a potential target for alleviating exercise-induced central fatigue.

Nrf2 activation by sequestosome1/p62 (p62) (Ser351) phosphorylation is a pivotal signal for the exercise-mediated augmentation of antioxidant protein expression in muscle. However, the molecular mechanisms regulating this signal in response to exercise remain unclear. In this study, we demonstrate that exercise training leads to higher levels of antioxidant proteins (e.g., CuZnSOD and EcSOD) in the mouse predominantly oxidative soleus, but not in the predominantly glycolytic white vastus lateralis muscle. We also observed that muscle-specific p62 overexpression, which leads to higher levels of phosphorylated (Ser351) p62, increases expression of these antioxidant proteins. Evidence for a cell-autonomous signal came from the observations that exercise training increased the expression of the neighbor of BRCA1 gene 1 (NBR1) protein, which is known to stimulate p62 (Ser351) phosphorylation, in the soleus muscle, whereas cyclic stretch of C2C12 myotubes led to the same outcomes. Of note, both exercise training in mice and cyclic stretch in myotubes enhanced the expression of cleaved interleukin-1β (IL-1β), which is known to stimulate NBR1 expression. A key upstream role for IL-1β in this signaling was then established by daily injections of IL-1β-neutralizing antibody, which prevented exercise training-mediated increases in NBR1, phosphorylated p62 (Ser351), and EcSOD in the soleus muscle. Collectively, these findings point to IL-1β as an important upstream modulator of NBR1, p62 phosphorylation, and increased antioxidant protein expression in the exercise-trained predominantly oxidative muscle.NEW & NOTEWORTHY Increased muscle contractile activity, such as in exercise, enhances antioxidant protein expression in muscles. Nrf2 activation by p62 phosphorylation at Ser351 is a pivotal signal for the exercise-mediated increase in antioxidant protein expression. However, the molecular mechanisms regulating p62 phosphorylation in response to exercise remain unclear. Here, we demonstrate that muscle-derived IL-1β modulates exercise-mediated increases in p62 (Ser351) phosphorylation in predominantly oxidative muscles, concomitant with increases in NBR1 protein.

Anuran amphibians have a unique body plan characterized by a high interstitial compliance as a consequence of numerous subcutaneous lymph sacs. Anurans produce lymph at very high rates owing to "leaky" capillaries and low capillary reflection coefficients. The copious amounts of formed lymph are stored in these lymph sacs but, owing to gravitational forces, lymph preferentially collects in the ventral lymph sacs. Lymph is returned to the circulation by dorsally located lymph hearts, which pump lymph into the venous side of the circulation. The major problem for anurans is moving the lymph from ventral lymph sacs, against gravity, to the dorsal lymph hearts. Lymph movement is accomplished by three distinct mechanisms: 1) horizontal movement of lymph along the hind limbs by differential lymph sac compliance; 2) vertical movement by skeletal muscles that insert on the urostyle, skin, and the margins of lymph sacs that change the compliance and pressure of lymph sacs; 3) lung ventilation and associated volume changes in the lungs are transmitted primarily to the subvertebral lymph sac overlying the lungs resulting in large negative pressures that aspirate lymph dorsally. Phylogenetic analyses reveal that lymph skeletal muscles have undergone bidirectional evolution with more terrestrial species showing greater elaboration of these muscles compared with aquatic species that have lost or reduced these muscles. More terrestrial species also have larger lung volumes and compliances than aquatic or semiaquatic anurans, which presumably enhance their ability to mobilize lymph movement in desiccating environments where maintenance of plasma volume is a greater challenge.

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.