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

This study aimed to determine the effects of an unexpected monetary reward on time-to-task failure (TTF) and on measures of performance and perceptual fatigability in healthy young adults. During two separate sessions, 18 participants (9 females) completed a TTF within the heavy-intensity domain (HVY_TTF), which was followed, after 1 min of rest, by a TTF within the extreme-intensity domain (EXT_TTF). In the second HVY_TTF session, an unexpected monetary reward was offered prior the self-anticipated task failure. Before and after each trial, neuromuscular fatigue was assessed at baseline (NMF_BSLN) and following HVY_TTF (NMF_HVY) and EXT_TTF (NMF_EXT) using femoral nerve stimulation during and after a quadriceps muscle isometric maximal voluntary contraction (IMVC). The unexpected monetary reward significantly increased HVY_TTF (46 ± 16 min vs. 53 ± 22 min; P = 0.011), while reducing the following EXT_TTF (68 ± 17 s vs. 57 ± 17 s; P = 0.034). IMVC (∼-31%), Db₁₀ (∼-42%), Db₁₀₀ (∼-21%), low-frequency fatigue (∼-26%), and potentiated twitch force (∼-37%) were all reduced from NMF_BSLN to NMF_HVY (P < 0.001) with no further declines following NMF_EXT (P > 0.005) except for Db₁₀ (∼-9%, P = 0.007) and potentiated twitch force (∼-9%; P < 0.001). Voluntary activation did not change from NMF_BSLN to NMF_HVY or from NMF_BSLN to NMF_EXT following either of the conditions (P > 0.005). These findings indicate that an unexpected monetary reward can increase exercise performance within the heavy-intensity domain. This improvement while being associated with no further reductions in neuromuscular indices of fatigue, it impaired subsequent extreme-intensity performance.NEW & NOTEWORTHY Exercise performance within the heavy-intensity domain was extended by an unexpected monetary reward offered when approaching task failure. The extended duration was not accompanied by further impairments in neuromuscular indices of fatigue nor changes in perceptual responses. However, subsequent exercise performance was reduced. Overall, these findings demonstrate a dissociation among different indices of performance and perceptual fatigability. Furthermore, they give a new perspective on how the type and time of a motivational strategy can influence training or competition performance.

Microglia, the resident immune cells of the central nervous system (CNS), play a pivotal role in monitoring neuronal activity, maintaining tissue homeostasis, and orchestrating immune responses. Under physiological conditions, microglia support neuronal survival and synaptic remodeling, in part through anti-inflammatory mechanisms and clearance of cellular debris. However, dysregulated microglial activation is implicated in a wide variety of pathologic states, including neurodegenerative diseases, stroke, and hypertension, largely through the induction of chronic neuroinflammation. Emerging evidence highlights the renin-angiotensin system (RAS) as a critical modulator of microglial activity. Microglia express most RAS components, including angiotensinogen, angiotensin-converting enzyme (ACE), ACE2, angiotensin II type 1 (AT₁R) and type 2 (AT₂R) receptors, and Mas1 receptor (Mas1R), enabling local generation of angiotensin peptides and autocrine/paracrine signaling. Activation of AT₁R leads toward proinflammatory reactive microglial phenotypes, characterized by elevated release of cytokines and reactive oxygen species, whereas AT₂R and Mas1R signaling transitions toward more homeostatic anti-inflammatory phenotypes, supporting tissue repair and neuronal protection. Dysregulation of this balance contributes to chronic neuroinflammation and may impact autonomic nervous system activity, linking microglial RAS signaling to systemic homeostatic alterations. Here, we review current literature into the expression, regulation, and functional consequences of RAS components in microglia, highlighting each element expression and signaling as regulators of neuroimmune activity while attempting to move away from the outdated M1/M2 nomenclature. We also discuss the therapeutic potential of pharmacologically targeting microglial RAS to shift reactive microglia toward a more homeostatic state, offering a promising strategy to mitigate neuroinflammation and protect against neurodegenerative and cardiovascular pathologies. Collectively, understanding the microglial RAS provides new avenues for intervention in CNS diseases associated with chronic inflammation.

Exercise intensity is often prescribed as a percentage of a "maximum" reference point. Both the choice of reference and the protocol to obtain it may bias apparent female-male differences in relative intensity. The objective of this study is to examine whether female-male differences in relative intensity expressed relative to a maximum reference [V̇o_2max or peak power output (PPO)] differ depending on the protocol used to determine it (ramp vs. step). Fifty trained cyclists (30 males, 20 females, 31 ± 8 yr old, V̇o_2max 3,866 ± 840 mL/min) completed a ramp-incremental and a 3-min step test on a cycle ergometer. Thresholds were determined in the step test from fixed and individualized blood lactate concentrations and from ventilation. Relative intensity was expressed in relation to PPO and V̇o_2max derived from each protocol. Linear mixed-effects models with participant as random intercept tested the fixed effects of Sex, Protocol, and their interaction. Agreement between ramp- and step-derived V̇o_2max values was evaluated using Bland-Altman analysis. For V̇o₂-based relative intensity, only protocol effects were small but significant (all P < 0.01). For Power, Sex had a significant influence in the models with males displaying higher relative intensities in all lactate-based thresholds (all P ≤ 0.02). Sex × Protocol interactions emerged for the onset of 2 mmol/L blood lactate (BLa₂) and Onset of minimum+ 0.5 mmol/l blood lactate (BLa_min+0.5) (both P < 0.05), indicating that using step or ramp protocols as reference can alter the magnitude or direction of female-male differences. Apparent sex differences in relative intensity depend on how "maximum" is defined and obtained. The same relative intensity does not ensure equivalent physiological strain across sexes.NEW & NOTEWORTHY Method matters when comparing men and women in exercise physiology. In trained cyclists, we show that apparent female-male differences in exercise intensity at lactate and ventilatory thresholds depend on how "maximum" is defined (V̇o_2max vs. peak power output) and the protocol used (ramp vs. step). Some sex effects appeared only under specific methodological choices, highlighting that differences often attributed to biology may, in fact, be artifacts of test design.

Increasing dietary nitrate (NO₃^-) through beetroot juice (BRJ) supplementation elicits acute ergogenic benefits. However, it is unknown whether chronic NO₃^- supplementation can enhance resistance training (RT) adaptations in middle-aged and older individuals. Therefore, we sought to determine whether 12 wk of combined RT and NO₃^- supplementation enhanced hypertrophic, vascular, strength, and skeletal muscle angiogenesis adaptations in this population. Twenty-eight apparently healthy, untrained men (M) and women (W) (56 ± 7 yr old and 29.1 ± 5.3 kg/m² body mass index) completed 12 wk of supervised full-body RT (2×/wk) while ingesting either BRJ (140 mL daily, providing 800 mg NO₃^-; n = 14 with 7 M/7 W) or NO₃^--depleted BRJ placebo (PLA; n = 14 with 7 M/7 W). Participants underwent a whole body dual-energy X-ray absorptiometry scan, right mid-thigh ultrasonography for muscle imaging, right leg popliteal artery flow-mediated dilation (FMD) assessments, a biopsy of the right mid-thigh vastus lateralis, and strength testing before and following the 12-wk intervention. Biopsy analyses included a NO₃^-/nitrite (NO_x) fluorometric assay, immunoblotting for proteins involved in angiogenesis, and immunohistochemistry to quantify fiber type-specific capillaries and cross-sectional areas. Muscle NO_x values did not significantly change: +15.4% in BRJ (P = 0.073) and +7.8% (P = 0.514) in PLA. Both groups significantly improved measures related to muscle hypertrophy, strength, and FMD. However, no significant group × time interactions were observed for whole body lean mass, mid-thigh muscle cross-sectional area, popliteal artery FMD outcomes, or histological or molecular markers. In conclusion, these preliminary data on a limited number of participants indicate that BRJ supplementation does not enhance RT adaptations in middle-aged and older adults.NEW & NOTEWORTHY Results from this study suggest that 12 wk of dietary nitrate supplementation does not significantly alter skeletal muscle hypertrophic, strength, or vascular outcomes in previously untrained middle-aged and older adults who performed resistance training.

Our studies have established that ureteric bud (UB) prorenin receptor (PRR/ATP6AP2), an accessory subunit of the vacuolar H⁺-ATPase (V-ATPase), is critical for normal UB branching. Here, we tested the hypothesis that V-ATPase activity, acidosis, and UB cell intracellular pH (pH_i) regulate UB branching morphogenesis during kidney development. The effect of specific V-ATPase inhibitor Bafilomycin, hypercapnic (high CO₂), and metabolic (low [Formula: see text]) acidosis on UB branching was determined in whole intact E12.5 Hoxb7^GFP+ mouse kidneys grown ex vivo by time-lapse photomicroscopy. The effect of Bafilomycin on UB cell migration in vitro was examined using a transwell migration assay (n = 3 wells/treatment group). The presence of V-ATPase and Na⁺-H⁺ exchanger (NHE) activity in UB cells was investigated by measurements of intracellular pH (pH_i). The ability of UB cells to regulate cell pH_i in vitro was determined by measurements of Na-dependent and Na-independent pH_i recovery from acid loads. The mean number of UB cells that migrated through the membrane after 24-h culture was reduced with Bafilomycin compared with control. Treatment with Bafilomycin, hypercapnic acidosis (induced by high CO₂), or metabolic acidosis (induced by low [Formula: see text] concentration) in the culture media caused a marked reduction in the number of UB tips compared with control. We conclude that intact V-ATPase activity is essential for normal UB branching during kidney development. V-ATPase-dependent reduction in UB cell pH_i is likely a cause of decreasing UB branching by inhibiting directional movements of UB cells.NEW & NOTEWORTHY Disruption of normal kidney development results in a spectrum of congenital anomalies of the kidney and urinary tract (CAKUT), the major cause of end-stage kidney disease in children. We demonstrate that acidosis, kidney cell intracellular pH, and activity of V-ATPase pump are essential for normal kidney development.

Introduction: We hypothesize that excessive central blood flow reduction leads to failure in the mechanism that appropriately distributes cerebral blood flow (CBF), preceding the pathological drop in blood pressure. This study aims to evaluate changes in CBF and cerebrovascular resistance in response to reduced cardiac output (CO) during severe central hypovolemia and elucidate the breakdown of cerebral circulation maintenance mechanisms before presyncope. Methods: Nine healthy men underwent maximal lower body negative pressure (LBNP), with ultrasound measurements of the internal carotid artery (ICA) and vertebral artery (VA) blood flow, and CO. Hemodynamic changes, including total peripheral resistance (TPR) and fractional CBF (CBF/CO), were assessed. Results: CO decreased from LBNP25%, while ICA and VA blood flow were preserved up to LBNP50% but declined from LBNP75%. CBF/CO increased until LBNP75%, then plateaued or slightly decreased. TPR increased from LBNP50% to LBNP75%, then plateaued. Both ICA-CVRi and VA-CVRi increased with higher LBNP loads. ICA-CVRi showed significant elevations at LBNP75% and LBNPpremax, whereas VA-CVRi reached a significantly higher value at LBNPpremax. Conclusion: The decrease in ICA and VA blood flow was smaller than that in CO. The maintenance of blood flow at higher LBNP loads is likely due to peripheral vascular constriction, but this compensatory mechanism failed at LBNP75%, just before presyncope.

The use of peripheral blood mononuclear cells (PBMCs) in cardiovascular research is increasingly common. However, little is known regarding potential age-related changes in mitochondrial bioenergetics and oxidative stress in PBMCs, or whether such changes relate to endothelial function. We assessed mitochondrial bioenergetics and antioxidant buffering capacity (AoxBC) capacity in PBMCs from young (n=18; 21±2 yrs) and older (n=17, 66±4 yrs) adults. High-resolution respirometry and fluorometry measured mitochondrial respiration rate (JO₂) and membrane potential (Δψm), respectively, in response to substrate provision (pyruvate/glutamate/malate/succinate; PGMS) and a bioenergetic creatine kinase (CK) clamp at physiological ATP:ADP ratios (PCr1, PCr2, and PCr3). MtROS emission was measured as hydrogen peroxide (H₂O₂) emission, and H₂O₂ production was quantified using inhibitors of glutathione reductase and thioredoxin/peroxiredoxin. AoxBC was calculated as the percentage of H₂O₂ produced but not emitted. Endothelial function was assessed via flow-mediated dilation (FMD). JO₂ was similar between groups at baseline (p=0.08) and lower energetic states (PCr2, PCr3; p≥0.09), but was lower in older adults at higher energetic states (PCr1: 14.05±2.11 vs. 12.03±2.98 pmol·sec^-1·10⁶ cells^-1, p=0.03; PGMS: 20.61±2.11 vs. 16.58±3.56 pmol·sec^-1·10⁶ cells^-1; p=0.0009). Δψm was hypo-polarized in older compared with young adults at all energetic states (p≤0.003). Although there were no statistical differences in H₂O₂ emission (p=0.43) or production (p=0.18), AoxBC was lower in older adults (52.59±15.44% vs. 63.49±10.30%; p=0.03). Age-related changes in JO₂ (PGMS, p=0.02) and Δψm (PGMS, p=0.0008; PCr2, p=0.04; PCr3, p=0.02) were related to FMD. These data demonstrate associations between altered PBMC mitochondrial bioenergetics and age-related vascular endothelial dysfunction.

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.

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.