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

There have been few studies that have examined hemodynamic responses to low-frequency neuromuscular electrical stimulation (LF-NMES), and the effects of combining passive cycle ergometry are still unclear. The purpose of this study was to examine the effects of a combination of LF-NMES and passive cycle ergometry on hemodynamic responses with a primary focus on the Fick principle in healthy adults. A randomized, crossover trial was conducted to evaluate the responses to three types of supine exercises (LF-NMES alone, LF-NMES with passive cycle ergometry, and voluntary cycle ergometry) adjusted to the same exercise intensity as the oxygen consumption of 14 mL/kg/min in 13 healthy adult men. Blood pressure, heart rate, blood lactate concentration, stroke volume (SV), cardiac output (CO), and left ventricular end-diastolic volume (LVEDV) were measured during each exercise in all subjects. The arterial-venous oxygenation difference (A-V̇o₂ difference) was calculated based on Fick's equation. LVEDV, SV, and CO were lower, and the A-V̇o₂ difference and blood lactate concentration were higher in LF-NMES alone than those in voluntary cycle ergometry and LF-NMES with passive cycle ergometry (P < 0.05). The blood lactate concentration was lower in LF-NMES with passive cycle ergometry than that in LF-NMES alone, but slightly higher than that in voluntary cycle ergometry (P < 0.05). Hemodynamic and metabolic responses of exercise with LF-NMES alone seemed consistent with insufficient peripheral perfusion based on the elevation of A-V̇o₂ difference and blood lactate concentration. The findings suggest that combining passive cycle ergometry with LF-NMES improves the insufficient peripheral perfusion induced by LF-NMES alone.NEW & NOTEWORTHY This is the first study to evaluate cardiac output, oxygen consumption, and A-V̇o₂ difference during LF-NMES of endurance exercise modality. LF-NMES alone may not demonstrate hemodynamic responses induced by voluntary endurance exercise, however, demonstrates those when combined with passive cycle ergometry. LF-NMES with passive cycle ergometry may be a more effective approach in cardiac rehabilitation for patients without the ability of voluntary exercise because it may increase cardiac output and venous return as represented by the LVEDV.

Marine teleosts experience ion gain and water loss in their natural habitats. Among other tissues, the urinary bladder epithelium of marine fishes has been shown to actively transport ions to facilitate water absorption. However, transport properties of the urinary bladder epithelium of marine fishes and its plasticity in altered ambient salinities is relatively under-investigated. We describe urinary bladder epithelium electrophysiology, water flux, and expressions of ion transporters in urinary bladder tissue of Gulf toadfish (Opsanus beta) acclimated to either 35 ppt or 60 ppt seawater. Water absorption in bladder sac preparations increased ∼350% upon acclimation to 60 ppt. Increases in water transport coincided with a significant ∼137% increase in urinary bladder tissue mucosal-to-serosal short circuit current (I_sc) and a ∼56% decrease in tissue membrane resistance. Collectively, these metrics indicate that an active electrogenic system facilitates water absorption via Na⁺ (and Cl^-) transport in urinary bladder tissue. Furthermore, pharmacological inhibition of urinary bladder tissue I_sc and expression of a suite of ion transporters and channels previously unidentified in this tissue provide mechanistic insights into the transport processes responsible for water flux. Analysis of water transport to overall Gulf toadfish water balance reveals a modest water conservation role for the urinary bladder of ∼0.5% of total water absorption in 35 ppt and 1.9% in 60 ppt acclimated toadfish. These results emphasize that electrogenic ion transport facilitates water-absorptive properties of the urinary bladder in Gulf toadfish-a process that is regulated to facilitate water homeostasis.NEW & NOTEWORTHY Novel experiments showcasing increased urinary bladder water absorption, ion transport, and altered channel/transporter expression in a marine fish acclimated to high salinities. Our results provide additional and noteworthy mechanistic insight into the ionoregulatory processes controlling water transport at the level of the urinary bladder in marine teleosts. Experimental outcomes are applied to whole organism-level water transport values, and the relative importance of marine teleost urinary bladder function to overall organism water conservatory measures is discussed.

Adaptations to skeletal muscle following resistance exercise are due in part to changes to the skeletal muscle transcriptome. Although transcriptional changes in response to resistance exercise occur in young and aged muscles, aging alters this response. Rodent models have served great utility in defining regulatory factors that underscore the influence of mechanical load and aging on changes to skeletal muscle phenotype. Unilateral eccentric contractions in young and aged rodents are widely used to model resistance exercises in humans. However, the extent to which unilateral eccentric contractions in young and aged rodents mimic the transcriptional response in humans remains unknown. We reanalyzed two publicly available RNA sequencing datasets from young and aged mice and humans that were subjected to acute eccentric contractions to define key similarities and differences in the muscle transcriptional response following this exercise modality. The effect of aging on the number of contraction-sensitive genes, the distribution patterns of those genes into unique/common categories, and the cellular pathways associated with the differentially expressed genes (DEGs) were similar in mice and humans. However, there was little overlap between species when comparing specific contraction-sensitive DEGs within the same age group. There were strong intraspecies relationships for the common transcription factors predicted to influence the contraction-sensitive gene sets, whereas interspecies relationships were weak. Overall, these data demonstrate key similarities between mice and humans for the contraction-induced changes to the muscle transcriptome, but we posit species-specific responses exist and should be taken into consideration when attempting to translate rodent eccentric exercise models.NEW & NOTEWORTHY Acute eccentric muscle contractions in rodents are used to model resistance exercise in young and aged humans, including changes to the muscle transcriptome. This work defines the utility of the rodent model at mimicking the transcriptional features observed in young and aged humans.

Age and sex may alter the cerebral blood flow (CBF) responses to acute isometric exercise, via associated elevations in mean arterial pressure (MAP) and sympathetic activation. Our aim was to determine the relationships between age, sex, and exercise intensity on cerebrovascular responses to isometric handgrip exercise. In 78 healthy adults (18-80 yr, n = 42 females), cerebrovascular responses were assessed during 2-min isometric exercise bouts at three intensities [15, 30, 45% maximal voluntary contraction (MVC)]. Intracranial responses of the middle cerebral artery (MCA) and posterior cerebral artery (PCA) velocity (v) were measured using transcranial Doppler ultrasound. Extracranial responses of the internal carotid artery (ICA) and vertebral artery (VA) were assessed using Duplex ultrasound. Cardiopulmonary hemodynamic and neural parameters were measured throughout, including muscle sympathetic nerve activity, end-tidal carbon dioxide, and MAP. There were significant positive relationships between exercise intensity and the cerebral responses of the MCAv (P < 0.001) and PCAv (P = 0.005). There were no effects of intensity on ICA and VA responses (P > 0.05), despite intensity-dependent increases in MAP (P < 0.001). The increased MCAv response to exercise was blunted with advancing age (P = 0.01) with no influence of sex (P = 0.86). The present study provides data on age, sex, and intensity-specific relationships with intracranial and extracranial cerebrovascular responses to isometric exercise. Despite similar ICA, VA, and PCA responses, MCAv responses were attenuated with advancing age during handgrip exercise with no sex-dependent influence. Furthermore, intracranial responses were intensity dependent, whereas extracranial blood flow, shear-stress, and velocity responses were similarly increased at all intensities during handgrip exercise.NEW & NOTEWORTHY The influence of aging and sex on cerebral blood flow responses to isometric exercise are unknown. We observed intensity-dependent increases in velocity of the intracranial arteries, whereas the extracranial artery responses were similarly increased at all intensities during handgrip exercise in young and older individuals. Furthermore, we observed a blunted middle cerebral artery velocity response to handgrip exercise with advancing age, whereas the posterior circulation and extracranial responses were preserved across the lifespan in healthy individuals in males and females alike.

Dehydration, characterized by the loss of total body water and/or electrolytes due to diseases or inadequate fluid intake, is prevalent globally but often underestimated. Its contribution to long-term chronic diseases and sarcopenia is recognized, yet the mechanisms involved in systemic and muscle protein metabolism during dehydration remain unclear. This study investigated metabolic adaptations in a 36-h water deprivation (WD) model of mice. Male C57BL/6 mice underwent 36-h WD or pair-feeding at rest, with assessments of motor skills along with biochemical and metabolic parameters. Dehydration was confirmed by hypernatremia, body mass loss, hyporexia, and increased activity of vasopressinergic and oxytocinergic neurons compared with controls. These results were associated with liver mass loss, decreased glycemia, and increased cholesterolemia. In addition, increased V̇o₂ and a decreased respiratory exchange ratio indicated reduced carbohydrate consumption and potentially increased protein use during dehydration. Thus, skeletal muscle protein metabolism was evaluated due to its high protein content. In the oxidative muscles of the WD group, total and proteasomal proteolysis increased, which was associated with decreased Akt-mediated intracellular signaling. Interestingly, there was an increase in fiber cross-sectional area, likely due to higher muscle water content caused by increased intracellular osmolality induced by protein catabolism products. Conversely, no changes were observed in protein turnover or water content in glycolytic muscles. These findings suggest that short-term WD imposes a procatabolic state, depleting protein content in skeletal muscle. However, skeletal muscle may respond differently to dehydration based on its phenotype and might adapt for a limited time.NEW & NOTEWORTHY This study investigated the effects of WD on mouse homeostasis, focusing on energy substrates and skeletal muscle protein metabolism. Our findings revealed a shift toward reduced dependence on carbohydrate degradation and increased reliance on lipid oxidation, or even protein oxidation, as energy sources, since we observed increased proteolysis in one muscle phenotype. Despite body mass loss, soleus and EDL muscle masses were differently affected. These results indicate the procatabolic potential of short-term WD in mice.

Factors explaining individual variations in whole body sweat sodium ion concentration ([Na⁺]) during exercise are not fully understood. Galvanic skin conductance (GSC) reflects the electrical properties of the skin influenced by sweat rate (SR) and the presence of ions. Initiation of increases in this response to elevating sweating may reflect exceeding the maximal capacity of sweat ion reabsorption in sweat glands. We investigated whether the SR threshold for increasing GSC, an indirect measure of maximum ion reabsorption rates of sweat glands, explains the variations in whole body sweat [Na⁺]. Thirty young healthy males cycled for 90 min at incremental exercise intensities of 30, 45, and 60% peak oxygen uptake (30 min each) in the heat (32°C, 50% relative humidity). Whole body sweat [Na⁺] was measured using a whole body washdown technique. The SR threshold for increasing GSC was determined from the relationship between the local SR (ventilated capsule) and GSC on the forearm and chest. The average whole body sweat [Na⁺] was 42.8 ± 18.9 (range: 14.4-81.0) mmol L^-1, and the SR threshold for increasing GSC was 0.29 ± 0.20 (range: 0.02-0.62) and 0.35 ± 0.30 (range: 0.01-1.40) mg cm^-2 min^-1 for the forearm and chest, respectively. Whole body sweat [Na⁺] was not correlated with the SR threshold for increasing GSC in the forearm or chest (r² ≤ 0.001, P ≥ 0.921). We conclude that the SR threshold for increasing GSC at the forearm and chest does not explain the individual variation in whole body sweat [Na⁺] during exercise in the heat.NEW & NOTEWORTHY Galvanic skin conductance is influenced by sweat rate and sweat ions, and the sweat rate at which this response begins to increase may reflect the exceeding capacity of sweat ion reabsorption in sweat glands. However, we show that this indirect measure of the sweat gland's capacity of ion regulation on the forearm and chest does not correlate with whole body sweat sodium concentration during exercise, excluding its role as a determinant of systemic sweat sodium loss.

Vagal sensory afferents carrying information from the gastrointestinal tract (GI) terminate in the nucleus of the solitary tract (NTS). Different subpopulations of NTS neurons then relay this information throughout the brain. Cholecystokinin (CCK) is a satiety peptide that activates vagal afferents in the GI. However, CCK is also expressed by neurons in the NTS, and activation of these neurons decreases food intake. What is less clear is how these NTS CCK neurons are activated by vagal afferents and what type of information they integrate about meal size and content. To address this, we identified NTS-CCK neurons by crossing CCK-IRES-Cre mice with floxed-Rosa-tdtomato mice and made a horizontal brain slice containing vagal afferents in the solitary tract (ST). Voltage clamp recordings of NTS-CCK neurons show that activation of the ST evokes excitatory postsynaptic currents (EPSCs) mediated by both α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) and N-methyl-d-aspartate (NMDA) receptors. Analysis of these EPSCs revealed that 80% of NTS-CCK neurons receive direct, monosynaptic inputs, with many also receiving indirect, or polysynaptic, inputs. NTS-CCK neurons are sensitive to the transient receptor potential vanilloid type 1 agonist capsaicin, suggesting that they are downstream of C-fibers. In addition, both CCK and a 5 hydroxytryptamine 3 receptor (5-HT3R) agonist increased spontaneous EPSC (sEPSC) frequency in NTS-CCK neurons, with 69% of NTS-CCK neurons sensitive to CCK and 42% to the 5-HT3 receptor agonist, as well as 45% sensitive to both and 10% to neither. Taken together with previous studies, this suggests that NTS-CCK neurons are driven primarily by vagal afferents that are sensitive to CCK and are only weakly driven by those sensitive to serotonin.NEW & NOTEWORTHY Nucleus of the solitary tract (NTS) cholecystokinin (CCK) expressing neurons are directly activated by glutamate released from vagal afferents. They are downstream of primarily C-type CCK-sensitive afferents, with a small proportion also downstream of serotonin-sensitive afferents. These findings suggest that NTS-CCK neurons integrate signals from the gut about ingestion of fats and proteins as well as stretch of the stomach, which they then relay to other brain regions important for the control of food intake.

Preterm birth increases the risk of cardiometabolic disease in adulthood. Infants born during the second trimester of pregnancy, a critical period of hypothalamic development, are at risk of sodium (Na) depletion due to renal immaturity and large urine Na losses. We previously demonstrated in male mice that Na restriction during the equivalent mouse hypothalamic development period [postnatal day (PD)21-PD42] programs long-term changes in energy balance via increased thermogenic sympathetic nervous activity. We therefore hypothesized that early-life Na restriction programs changes in cardiovascular control via altered autonomic activity. C57BL/6J male mice were supplied a low (0.04%) Na or supplemented (0.30%) Na diet from PD21 to PD42, before return to standard (0.15%) Na diet. Hemodynamic and autonomic functions were assessed by radiotelemetry and acute administration of autonomic antagonists before and after all animals were switched to a high Na diet (HSD; 1% Na) at 12 wk of age. Mice were additionally treated with the angiotensin II type 1 receptor antagonist losartan for 2 wk. On standard diet, early-life Na restriction resulted in small but significantly different hemodynamic responses to autonomic blockers without any effect on systolic blood pressure (SBP) or heart rate. HSD increased SBP in 0.04% but not 0.30% Na mice, accompanied by increased cardiac sympathetic activity. Losartan had a greater BP-lowering effect in early-life Na-restricted mice. Our findings suggest that Na restriction during a critical hypothalamic developmental period programs long-term changes in the autonomic control of cardiovascular functions and may offer insight into the increased risk of cardiovascular disease in former preterm infants.NEW & NOTEWORTHY Mechanisms by which preterm birth increases the risk of adult-onset cardiometabolic diseases are not well understood. The renin-angiotensin system (RAS) has been implicated in the programming of adult disease, although contributors to RAS dysregulation remain to be identified. Findings from this study suggest that failure to maintain postnatal sodium homeostasis during a critical developmental window may contribute to RAS dysregulation and the risk of salt sensitivity of autonomic and cardiovascular function.

Hypobaric hypoxia (HH) occurring at high altitudes activates the sympathetic nervous system (SNS) and increases circulating erythropoietin (EPO) levels. EPO stimulates red blood cell production (erythropoiesis), enhancing oxygen transport in arterial blood to counteract hypoxemia. The present study tested the hypothesis that SNS contributes to EPO activation by HH through epinephrine (EPI) release from the adrenal medullae. Adult male C57B6 mice were exposed to 18 h of HH (0.4 atm), and renal EPO mRNA and plasma EPO levels were measured. HH increased EPO mRNA and plasma EPO levels, and SNS activation, as indicated by elevated plasma norepinephrine (NE) and EPI levels. In adrenal-medullectomized mice, HH-induced EPO response was reduced, correlating with decreased circulating NE and absence of EPI elevation. EPI, but not NE infusion, mimicked the effects of HH in room air-breathing mice. EPO responses to HH were reduced with β-adrenergic receptor (AR) blockade using dl-propranolol and in β2 adrenergic receptor knockout mice. Mice with heterozygous Hif-2α deficiency (Hif-2α^+/-), but not Hif-1α^+/-, showed attenuated EPO gene activation and elevated plasma EPO levels in response to HH and EPI infusion. These results demonstrate that adrenal EPI facilitates the EPO gene activation by HH through the interaction of β2 AR with HIF-2α.NEW & NOTEWORTHY Hypobaric hypoxia activates the sympathetic nervous system (SNS) and the erythropoietin (EPO) gene. Whether SNS activation by hypoxia influences the EPO gene activation is an unresolved question. The present study demonstrates that adrenal epinephrine facilitates hypoxia-induced EPO gene activation through the interaction of β2 adrenergic receptors (β2 ARs) with the transcriptional activator HIF-2α.

The process of autophagy is vital in maintaining normal cellular function, especially during exposure to elevated states of physiological stress associated with exercise and hot ambient temperatures. Although prior observations are primarily limited to responses in males, the autophagic response to acute physiological stress in females represents a considerable knowledge gap. Therefore, we assessed autophagy and related pathways of cellular stress in peripheral blood mononuclear cells (PBMCs) from 20 healthy young [n = 10, mean (SD): aged 23 yr (3)] and older [n = 10, aged 69 yr (3)] females in response to 30 min of semi-recumbent high-intensity cycling exercise (70% of predetermined maximal oxygen consumption) in temperate (25°C) and hot (40°C) ambient conditions (15% relative humidity). Mean body temperature (rectal and skin) was measured throughout, whereas cellular responses were evaluated before and after exercise, including up to 6 h of seated recovery. Proteins associated with autophagy and related pathways were assessed via Western blot. Mean body temperature was elevated after exercise in both conditions, with significant elevations observed after exercise in the heat (all, P ≤ 0.05). Although young females displayed signs of elevated autophagic activity [elevations in microtubule-associated light chain 3B (LC3)-II and beclin-2] in response to exercise performed in both temperate and hot ambient conditions (all, P ≤ 0.05), responses were attenuated in older females. This was accompanied by elevations in chaperone-mediated autophagy in young but not in older females in response to exercise independent of ambient temperature. Our findings indicate exercise, with and without ambient heat exposure may stimulate the autophagic response in young but not in older females.NEW & NOTEWORTHY We show for the first time that an acute bout (30 min) of high-intensity intensity exercise stimulates autophagy in young females irrespective of ambient heat exposure. However, older females did not display the same increase in autophagy as their younger counterparts when high-intensity exercise was performed in temperate or hot ambient conditions. Consequently, older females may be at an elevated risk of heat-induced cellular damage during exertional heat stress.