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NEW FINDINGS: What is the central question of this study? Ischaemic preconditioning is a novel pre-exercise priming strategy. We asked whether ischaemic preconditioning would alter mitochondrial respiratory function and pulmonary oxygen uptake kinetics and improve severe-intensity exercise performance. What is the main finding and its importance? Ischaemic preconditioning expedited overall pulmonary oxygen uptake kinetics and appeared to prevent an increase in leak respiration, proportional to maximal electron transfer system and ADP-stimulated respiration, that was evoked by severe-intensity exercise in sham-control conditions. However, severe-intensity exercise performance was not improved. The results do not support ischaemic preconditioning as a pre-exercise strategy to improve exercise performance in recreationally active participants. ABSTRACT: We examined the effect of ischaemic preconditioning (IPC) on severe-intensity exercise performance, pulmonary oxygen uptake ( V ̇ O 2 ${\dot V_{{{\rm{O}}_{\rm{2}}}}}$ ) kinetics, skeletal muscle oxygenation (muscle tissue O2 saturation index) and mitochondrial respiration. Eight men underwent contralateral IPC (4 × 5 min at 220 mmHg) or sham-control (SHAM; 20 mmHg) before performing a cycling time-to-exhaustion test (92% maximum aerobic power). Muscle (vastus lateralis) biopsies were obtained before IPC or SHAM and ∼1.5 min postexercise. The time to exhaustion did not differ between SHAM and IPC (249 ± 37 vs. 240 ± 32 s; P = 0.62). Pre- and postexercise ADP-stimulated (P) and maximal (E) mitochondrial respiration through protein complexes (C) I, II and IV did not differ (P > 0.05). Complex I leak respiration was greater postexercise compared with baseline in SHAM, but not in IPC, when normalized to wet mass (P = 0.01 vs. P = 0.19), mitochondrial content (citrate synthase activity, P = 0.003 vs. P = 0.16; CI+IIP, P = 0.03 vs. P = 0.23) and expressed relative to P (P = 0.006 vs. P = 0.30) and E (P = 0.004 vs. P = 0.26). The V ̇ O 2 ${\dot V_{{{\rm{O}}_{\rm{2}}}}}$ mean response time was faster (51.3 ± 15.5 vs. 63.7 ± 14.5 s; P = 0.003), with a smaller slow component (270 ± 105 vs. 377 ± 188 ml min-1 ; P = 0.03), in IPC compared with SHAM. The muscle tissue O2 saturation index did not differ between trials (P > 0.05). Ischaemic preconditioning expedited V ̇ O 2 ${\dot V_{{{\rm{O}}_{\rm{2}}}}}$ kinetics and appeared to prevent an increase in leak respiration through CI, when expressed proportional to E and P evoked by severe-intensity exercise, but did not improve exercise performance.

This study aimed to evaluate the agreement of commonly reported energy metabolism measurements obtained from two different whole-room indirect calorimeters (WRICs).Nine healthy adult volunteers were evaluated over four separate 24-hour periods in a crossover design, twice in two different WRICs of different sizes, each operated according to the Room Indirect Calorimetry Operating and Reporting Standards published in 2020. The reproducibility of repeated measurements was quantified by the coefficient of variation (CV) and intraclass correlation coefficient (ICC).The CVs between and within each WRIC for average 24-hour carbon dioxide production rate (VCOCross-chamber reproducibility is high for common outcome measures assessed in the respiratory chamber. The results support efforts to promote standardization across WRICs to allow multicenter studies.

Cyclopoid and calanoid copepods differ in how they move. Cyclopoid copepods use the thoracic legs for cruise and escape swimming while most calanoid copepods use the cephalic appendages for cruise swimming and the thoracic legs for escape reactions. Apart from this gross difference, little is known on the comparative aspects of the locomotor function of copepod appendages. This study investigated the main kinematic patterns of cruise and escape swimming of two small cyclopoid copepods, Thermocyclops oithonoides and Oithona davisae, and a small calanoid copepod, Paracalanus parvus, by video filming at a frame rate of up to 1200 frames/s. During escape swimming, O. davisae and the twice as large P. parvus showed similar movement, jumping at a frequency of 150 Hz and moving at 12 cm s

Background One metabolic equivalent (MET) is equal to resting oxygen consumption. The average value for one MET in humans is widely quoted as 3.5ml/kg/min. However this value was derived from a single male participant at the end of the nineteenth century and has become canonical. Several small studies have identified varied estimates of one MET from widely varying populations. The ability of a patient to complete 4 METS (or 14mls/kg/min) is considered an indicator of their fitness to proceed to surgery. Aims The study aimed to define a typical value of one MET from a real-world patient population, as well as determine factors that influenced the value. Methods A database of cardiopulmonary exercise tests (CPET) tests was interrogated to find total of 1847 adult patients who had undergone CPET testing in the previous 10 years. From this database, estimates of oxygen consumption (VO2 ) at rest and at the anaerobic threshold and a number of other variables were obtained. The influence of age, body mass index (BMI), sex and the use of beta blockers was tested. Results The median resting VO2 at rest was 3.6ml/kg/min (IQR 3.0-4.2). Neither sex nor age greater than 65 years nor the use of beta blockers produced a significant difference in resting VO2 , while those with a BMI greater than 25 had a significantly lower VO2 at rest (3.4ml/kg/min vs 4.0ml/kg/min, p Conclusions The estimate of 3.6ml/kg/min for resting VO2 presented here is consistent with the previous literature, despite this being the first large study of its kind. This estimate can be safely used for pre-operative risk stratification. This article is protected by copyright. All rights reserved.

Whether gill area constrains fish metabolism through oxygen limitation is a debated topic. Here, the authors provide insights into this question by analysing mass-specific metabolic rates across 44 teleost fishes extracted from FishBase. They explore whether species deviations from metabolic rates predicted by body mass can be explained by species gill area. They show that the gill area explains c. 26%–28% of species-level deviations from mass-specific metabolic rates. Their findings suggest that gill area might indeed be one of the factors limiting metabolic rate in fishes.

We estimated genetic parameters of oxygen consumption (OC), OC per metabolic body weight (OCMBW), and body weight at three through eight weeks of age in divergently selected mice populations, with an animal model considering maternal genetic, common litter environmental, and cytoplasmic inheritance effects. Cytoplasmic inheritance was considered based on maternal lineage information. For OC, estimated direct heritability was moderate (0.32) and estimated maternal heritability and proportion of the variance of cytoplasmic inheritance effects to the phenotypic variance were very low (both Ndufa12, Sdhc, Atp10b, etc.),Prr16encoding Largen protein,Cry1encoding a key component of the circadian core oscillator, and so on. The results could contribute to elucidate the genetic mechanism of OC, an indicator for maintenance energy requirement and therefore feed efficiency.

The human brain constitutes 2% of the body's total mass but uses 20% of the oxygen. The rate of the brain's oxygen utilization can be derived from a knowledge of cerebral blood flow and the oxygen extraction fraction (OEF). Therefore, OEF is a key physiological parameter of the brain's function and metabolism. OEF has been suggested to be a useful biomarker in a number of brain diseases. With recent advances in MRI techniques, several MRI-based methods have been developed to measure OEF in the human brain. These MRI OEF techniques are based on the T

The importance of using masks during exercise has increased since the coronavirus disease-2019 (COVID-19). This study aimed to investigate the effects of using surgical masks on gas exchange and exercise responses in maximal exercise. Twenty-six participants were included. Participants performed the maximal exercise tests twice, masked, and unmasked. Gas exchange parameters (at maximal exercise and anaerobic threshold [AT]) and hemodynamic responses were measured. In the hemodynamic responses measured at rest, only the saturation of peripheral oxygen (SpO(2)) was lower in the masked (mean: 97.23 +/- 1.33%) measurement than in the unmasked (mean: 97.96 +/- 1.07%) measurement (p = 0.006). Test duration was lower in the masked test (unmasked: 10.32 +/- 1.36 min vs. masked: 10.03 +/- 1.42 min, p = 0.030). Peak oxygen consumption (VO2peak) (unmasked: 31.23 +/- 5.37 vs. masked: 27.03 +/- 6.46 ml/kg/min), minute ventilation (V-E) l/min, and energy expenditure (EE) kcal/hour were higher in unmasked tests (p < 0.001). There was no difference in the gas exchange parameters measured at the AT in the masked and unmasked tests (p > 0.05). Respiratory gas exchange parameters were affected in peak exercise due to increased respiratory workload, but not at the AT. There was no change in hemodynamic responses because vascular control may not be affected by mask usage.

The energetics of cycling represents a well-studied area of exercise science, yet there are still many questions that remain. Efficiency, broadly defined as the ratio of energy output to energy input, is one key metric that, despite its importance from both a scientific as well as performance perspective, is commonly misunderstood. There are many factors that may affect cycling efficiency, both intrinsic (e.g., muscle fiber type composition) and extrinsic (e.g., cycling cadence, prior exercise, and training), creating a complex interplay of many components. Due to its relative simplicity, the measurement of oxygen uptake continues to be the most common means of measuring the energy cost of exercise (and thus efficiency); however, it is limited to only a small proportion of the range of outputs humans are capable of, further limiting our understanding of the energetics of high-intensity exercise and any mechanistic bases therein. This review presents evidence that delta efficiency does not represent muscular efficiency and challenges the notion that the slow component of oxygen uptake represents decreasing efficiency. It is noted that gross efficiency increases as intensity of exercise increases in spite of the fact that fast-twitch fibers are recruited to achieve this high power output. Understanding the energetics of high-intensity exercise will require critical evaluation of the available data.

Coronary blood flow is tightly regulated to ensure that myocardial oxygen delivery meets local metabolic demand via the concurrent action of myogenic, neural and metabolic mechanisms. Although several competing hypotheses exist, the specific nature of the local metabolic mechanism(s) remains poorly defined. To gain insights into the viability of putative metabolic feedback mechanisms and into the co-ordinated action of parallel regulatory mechanisms, we applied a multiscale modelling framework to analyse experimental data on coronary pressure, flow and myocardial oxygen delivery in the porcine heart in vivo. The modelling framework integrates a previously established lumped-parameter model of myocardial perfusion used to account for transmural haemodynamic variations and a simple vessel mechanics model used to simulate the vascular tone in each of three myocardial layers. Vascular tone in the resistance vessel mechanics model is governed by input stimuli from the myogenic, metabolic and autonomic control mechanisms. Seven competing formulations of the metabolic feedback mechanism are implemented in the modelling framework, and associated model simulations are compared with experimental data on coronary pressures and flows under a range of experimental conditions designed to interrogate the governing control mechanisms. Analysis identifies a maximally probable metabolic mechanism among the seven tested models, in which production of a metabolic signalling factor is proportional to myocardial oxygen consumption and delivery is proportional to flow. Finally, the identified model is validated based on comparisons of simulations with data on the myocardial perfusion response to conscious exercise that were not used for model identification. KEY POINTS: Although several competing hypotheses exist, we lack knowledge of specific nature of the metabolic mechanism(s) governing regional myocardial perfusion. Moreover, we lack an understanding of how parallel myogenic, adrenergic/autonomic and metabolic mechanisms work together to regulatory oxygen delivery in the beating heart. We have developed a multiscale modelling framework to test competing hypotheses against experimental data on coronary pressure, flow and myocardial oxygen delivery in the porcine heart in vivo. The analysis identifies a maximally probable metabolic mechanism among seven tested models, in which the production of a metabolic signalling factor is proportional to myocardial oxygen consumption and delivery is proportional to flow.

International audience; Tree stem respiration (R S) is a substantial component of the forest carbon balance. The mass balance approach uses stem CO 2 efflux and internal xylem fluxes to sum up R S , while the oxygen-based method assumes O 2 influx as a proxy of R S. So far, both approaches have yielded inconsistent results regarding the fate of respired CO 2 in tree stems, a major challenge for quantifying forest carbon dynamics. We collected a data set of CO 2 efflux, O 2 influx, xylem CO 2 concentration, sap flow, sap pH, stem temperature, nonstructural carbohydrates concentration and potential phosphoenolpyruvate carboxylase (PEPC) capacity on mature beech trees to identify the sources of differences between approaches. The ratio of CO 2 efflux to O 2 influx was consistently below unity (0.7) along a 3-m vertical gradient, but internal fluxes did not bridge the gap between influx and efflux, nor did we find evidence for changes in respiratory substrate use. PEPC capacity was comparable with that previously reported in green current-year twigs. Although we could not reconcile differences between approaches, results shed light on the uncertain fate of CO 2 respired by parenchyma cells across the sapwood. Unexpected high values of PEPC

The effects of short sprint interval training (sSIT) with efforts of ≤10 s on maximal oxygen consumption (V̇O

Aims The minute ventilation–carbon dioxide production relationship (VE/VCO2 slope) is widely used for prognostication in heart failure (HF) with reduced left ventricular ejection fraction (LVEF). This study explored the prognostic value of VE/VCO2 slope across the spectrum of HF defined by ranges of LVEF. Methods and results In this single‐centre retrospective observational study of 1347 patients with HF referred for cardiopulmonary exercise testing, patients with HF were categorized into HF with reduced (HFrEF, LVEF

This study was designed to (1) investigate the effects of acute exercise under intermittent hypoxia on muscle mRNA and protein levels, and (2) clarify the mechanisms by which exercise under intermittent hypoxia improves endurance capacity. Experiment-1: Male mice were subjected to either acute endurance exercise, exercise under hypoxia (14% O

NEW FINDINGS What is the central question of this study? During exercise, there are fluctuations in conduit artery blood flow (BF) caused by both cardiac and muscle contraction-relaxation cycles. What is the optimal method to process Doppler ultrasound-measured BF for the purpose of characterizing the dynamic response of BF during step-transitions in exercise? What is the main finding and its importance? Continuous BF data were processed in relation to either cardiac or muscle contraction-relaxation cycles and computed based on 'binned' or 'rolling' averages over one, two or five consecutive cycles. Kinetics characterization revealed no data processing technique-specific differences in steady-state BF, but variability in the rapidity at which BF attained steady-state (i.e., mean response time) was observed. ABSTRACT The overall rate of blood flow (BF) adjustment (i.e., kinetics) from the onset of an exercise transition can be quantified by the mean response time (MRT). However, the BF response profile can be distorted during rhythmic, dynamic exercise consequent to variations caused by the cardiac cycle (HR) and the muscle contraction-relaxation (CR) cycle. We examined the extent to which distortions imposed by HR and CR cycles affected BF kinetics. Eight healthy, young men (27 (4) years; mean (SD)) performed transitions of alternate-leg knee-extension exercise from 3 W to either a moderate- (MOD) or heavy-intensity (HVY) power output. Femoral artery BF was continuously measured by Doppler ultrasound and averaged over one, two or five 'binned' (e.g., HR2b, etc.) or 'rolling' (e.g., CR5r, etc.) HR and CR cycles. Among analysis techniques, there were no differences for steady-state BF values at the 3 W baseline. In MOD, MRT using contraction-relaxation cycle (CR1) was smaller than most other analysis techniques. For both MOD and HVY, the 95% confidence interval for MRT was generally larger when using HR- compared to CR-related methods, and monoexponential fits based on 'rolling' averages (HR2r, HR5r, CR2r, CR5r) had a poorer ability to estimate the true end-exercise BF in HVY than in MOD. When modelling BF kinetics, we conclude that the CR1 method is a good option because of its ability to accurately estimate the 'data-determined' end-exercise BF value from the 'model-derived' response, maintain a relatively high density of data points during the transition and yield a relatively small 95% CI.

The aim of this study was to investigate the effects of four different training periodizations, based on two different training intensity distributions during a 16-week training block in well-trained endurance runners. Sixty well-trained male runners were divided into four groups. Each runner completed one of the following 16-week training interventions: a pyramidal periodization (PYR); a polarized periodization (POL); a pyramidal periodization followed by a polarized periodization (PYR → POL); and a polarized periodization followed by a pyramidal periodization (POL → PYR). The PYR and POL groups trained with a pyramidal or polarized distribution for 16 weeks. To allow for the change in periodization for the PYR → POL and POL → PYR groups, the 16-week intervention was split into two 8-week phases, starting with pyramidal or polarized distribution and then switching to the other. The periodization patterns were isolated manipulations of training intensity distribution, while training load was kept constant. Participants were tested pre-, mid- and post-intervention for body mass, velocity at 2 and 4 mmol·L-1 of blood lactate concentration (vBLa2, vBLa4), absolute and relative peak oxygen consumption ( V˙O2peak ) and 5-km running time trial performance. There were significant group × time interactions for relative V˙O2peak (p

This parallel-groups randomised controlled trial investigated the effect of concurrent strength and endurance (CSE) training on running performance, biomechanics, and muscle activity during overground running. Thirty moderately-trained distance runners were randomly assigned to 10-weeks CSE training (n = 15; 33.1 ± 7.5 years) or a control group (n = 15; 34.2 ± 8.2 years). Participants ran ≥ 30 km per week and had no experience with strength training. The primary outcome measure was two-kilometre run time. Secondary outcome measures included lower limb sagittal plane biomechanics and muscle activity during running (3.89 m·s-1 and maximal sprinting); maximal aerobic capacity (VO2 max); running economy; and, body composition. CSE training improved two-kilometre run time (mean difference (MD): -11.3 s [95% CI -3.7, -19.0]; p = 0.006) and time to exhaustion during the VO2 max running test (MD 59.1 s [95% CI 8.58, 109.62]; p = 0.024). The CSE training group also reduced total body fat (MD: -1.05 kg [95% CI -0.21, -1.88]; p = 0.016) while total body mass and lean body mass were unchanged. Hip joint angular velocity during the early swing phase of running at 3.89 m·s-1 was the only biomechanical or muscle activity variable that significantly changed following CSE training. CSE training is beneficial for running performance, but changes in running biomechanics and muscle activity may not be contributing factors to the performance improvement. Future research should consider other possible mechanisms and the effect of CSE training on biomechanics and muscle activity during prolonged running under fatigued conditions.

We aimed at examining the impact of wearing surgical face masks on exercise performance. Thirty‐two healthy adults (16 males and 16 females) completed a graded exercise test to measure peak oxygen uptake (VO2peak) and the ventilatory threshold (VT). Then, on separate days, all participants performed resting and standardized protocols (moderate intensity: 25% infra‐VT; severe intensity: 25% supra‐VT) on two different conditions (with and without a surgical mask). The use of masks reduced both VO2 and minute ventilation during moderate and severe exercise (p

Estimating metabolic rate in wild, free-swimming fish is inherently challenging. Here, we explored using surgically implanted heart rate biologgers to estimate metabolic rate in two warmwater piscivores, bowfin Amia calva (Linneaus 1766) and largemouth bass Micropterus salmoides (Lacepede 1802). Fish were surgically implanted with heart rate loggers, allowed to recover for 24 h, exposed to a netting and air exposure challenge, and then placed into respirometry chambers so that oxygen consumption rate (ṀO2 ) could be measured in parallel to heart rate (fH ) for a minimum of 20 h (ca. 20 estimates of ṀO2 ). Heart rate across the duration of the experiment (at 19°C) was significantly higher in largemouth bass (mean ± s.d., 45 ± 14 beats min-1 , range 18-86) than in bowfin (27 ± 9 bpm, range 16-98). Standard metabolic rate was also higher in largemouth bass (1.06 ± 0.19 mg O2 kg-1 min-1 , range 0.46-1.36) than in bowfin (0.89 ± 0.17 mg O2 kg-1 min-1 , range 0.61-1.28). There were weak relationships between fH and ṀO2 , with heart rate predicting 28% of the variation in oxygen consumption in bowfin and 23% in largemouth bass. The shape of the relationship differed somewhat between the two species, which is perhaps unsurprising given their profound differences in physiology and life history, illustrating the need to carry out species-specific validations. Both species showed some potential for a role of fH in efforts to estimate field metabolic rates, although further validation experiments with a wider range of conditions (e.g., digestive states, swimming activity) would likely help improve the strength of the ṀO2 -fH relationship for use in field applications.

BACKGROUND Poor cardiorespiratory fitness (CRF) is a cardinal feature of post-treatment primary lung cancer. The most effective exercise therapy regimen to improve CRF has not been determined. METHODS In this parallel-group factorial randomized controlled trial, lung cancer survivors with poor CRF (below age-sex sedentary values) were randomly allocated to receive 48 consecutive supervised sessions thrice weekly of (i) aerobic training (AT)-cycle ergometry at 55% to >95% of peak oxygen consumption (VO2 peak); (ii) resistance training (RT)-lower and upper extremity exercises at 50-85% of maximal strength; (iii) combination training (CT)-AT plus RT; or (iv) stretching attention control (AC) for 16 weeks. The primary endpoint was change in CRF (VO2 peak, mL O2 ·kg-1 ·min-1 ). Secondary endpoints were body composition, muscle strength, patient-reported outcomes, tolerability (relative dose intensity of exercise), and safety. Analysis of covariance determined change in primary and secondary endpoints from baseline to post-intervention (Week 17) with adjustment for baseline values of the endpoint and other relevant clinical covariates. RESULTS Ninety patients (65 ± 9 years; 66% female) were randomized (AT, n = 24; RT, n = 23; CT, n = 20; and AC, n = 23) of the planned n = 160. No serious adverse events were observed. For the overall cohort, the lost-to-follow-up rate was 10%. Mean attendance was ≥75% in all groups. In intention-to-treat analysis, VO2 peak increased 1.1 mL O2 ·kg-1 ·min-1 [95% confidence interval (CI): 0.0, 2.2, P = 0.04] and 1.4 mL O2 ·kg-1 ·min-1 (95% CI: 0.2, 2.5, P = 0.02) in AT and CT, respectively, compared with AC. There was no difference in VO2 peak change between RT and AC (-0.1 mL O2 ·kg-1 ·min-1 , 95% CI: -1.2, 1.0, P = 0.88). Favourable improvements in maximal strength and body composition were observed in RT and CT groups compared with AT and AC groups (Ps

PURPOSE Whether the modified shuttle test (MST) achieves maximal effort in children and adolescents with asthma is unclear. The aim was to compare the physiological responses of MST to the cardiopulmonary exercise test (CPET) in pediatric patients with asthma, to observe its convergent validity. PATIENTS AND METHODS A cross-sectional study with volunteers with asthma (6-17 years of age) under regular treatment. The MST is an external-paced test, and the participants were allowed to walk/run. CPET was performed on a cycle ergometer to compare with MST. Gas exchange (VO2 , VCO2 , and VE) and heart rate (HR) were the outcomes and were continuously assessed in both tests. RESULTS Forty-seven volunteers were included, normal lung function expiratory forced volume at 1st second/forced vital capacity (FEV1 /FVC) 88.6 (7.7). VO2peak was higher at MST (2.0 ± 0.6 L/min) compared to CPET (1.6 ± 0.5 L/min), p

Introduction/Aims: Aerobic deconditioning, due to lower levels of physical activity, could impact independence for people with neuromuscular conditions. We report the maximal cardiopulmonary response in a cohort of people with Charcot Marie Tooth disease type 1A (CMT 1A) and inclusion body myositis (IBM). We also explored potential predictors of aerobic capacity with measures of physical impairment and functional performance.\ud \ud Methods: Participants underwent maximal cardiopulmonary exercise testing (CPET) using a semi-recumbent cycle ergometer. Data were analyzed to determine the peak O2 consumption (VO2 peak), anaerobic threshold (AT), maximum heart rate (MHR), ventilatory equivalent for CO2 slope (VE/VCO2), and respiratory exchange ratio (RER). Impairment, functional and patient reported measures were also recorded. Predicted CPET variables were calculated based on published normative data for age, gender, and weight.\ud \ud Results: Twenty-two people with CMT and 17 people with IBM were recruited. Both groups showed significantly lower VO2 peak, MHR, AT, and VE/VCO2. The CMT group overall performed better than the IBM group, with significantly higher VO2 peak, MHR, and AT, but lower VE/VCO2. Linear regression analysis demonstrated that VO2 peak was related to body fat percentage and 6-min walk distance for both groups, and steps per day for the IBM group.\ud \ud Discussion: Lower than predicted CPET variables were observed that were not explained by cardiopulmonary limitations or reduced effort, implicating peripheral factors in limiting the cycling task. Regression analysis implied prediction of VO2 peak by body fat percentage and 6-min walk distance. Six-minute walk distance could be a potential proxy measure of cardiopulmonary fitness.

BACKGROUND Although depressive symptoms are associated with an increased risk of readmission after left ventricular assist device (LVAD) implantation, it is unclear whether they affect the efficacy of exercise-based cardiac rehabilitation (EBCR). This study aimed to investigate the effect of depressive symptoms on EBCR efficacy. METHODS We analyzed 48 patients who participated in EBCR after LVAD implantation (mean age 45 ± 12 years; 60% male). Patients were classified into two groups using the Zung Self-Rating Depression Scale (SDS): depressive group (SDS ≥40, n = 27) and non-depressive group (SDS

The cerebral microcirculation undergoes dynamic changes in parallel with the development of neurons, glia, and their energy metabolism throughout gestation and postnatally. Cerebral blood flow (CBF), oxygen consumption, and glucose consumption are as low as 20% of adult levels in humans born prematurely but eventually exceed adult levels at ages 3 to 11 years, which coincide with the period of continued brain growth, synapse formation, synapse pruning, and myelination. Neurovascular coupling to sensory activation is present but attenuated at birth. By 2 postnatal months, the increase in CBF often is disproportionately smaller than the increase in oxygen consumption, in contrast to the relative hyperemia seen in adults. Vascular smooth muscle myogenic tone increases in parallel with developmental increases in arterial pressure. CBF autoregulatory response to increased arterial pressure is intact at birth but has a more limited range with arterial hypotension. Hypoxia-induced vasodilation in preterm fetal sheep with low oxygen consumption does not sustain cerebral oxygen transport, but the response becomes better developed for sustaining oxygen transport by term. Nitric oxide tonically inhibits vasomotor tone, and glutamate receptor activation can evoke its release in lambs and piglets. In piglets, astrocyte-derived carbon monoxide plays a central role in vasodilation evoked by glutamate, ADP, and seizures, and prostanoids play a large role in endothelial-dependent and hypercapnic vasodilation. Overall, homeostatic mechanisms of CBF regulation in response to arterial pressure, neuronal activity, carbon dioxide, and oxygenation are present at birth but continue to develop postnatally as neurovascular signaling pathways are dynamically altered and integrated. © 2021 American Physiological Society. Compr Physiol 11:1-62, 2021.

NEW FINDINGS What is the central question of this study? Does impairment in the dynamics of O2 transport in skeletal muscle during a series of contractions constitute a potential mechanism underlying reduced exercise capacity in pulmonary hypertension? What is the main finding and its importance? Pulmonary hypertension compromises the dynamic matching of skeletal muscle O2 delivery-to-utilization following contraction onset in the rat spinotrapezius muscle. These results implicate a role for vascular dysfunction in the slow VO2 kinetics and exercise intolerance present in pulmonary hypertension. ABSTRACT Pulmonary hypertension (PH) is characterized by pulmonary vascular dysfunction and exercise intolerance due, in part, to compromised pulmonary and cardiac function. We tested the hypothesis that there are peripheral (i.e., skeletal muscle) aberrations in O2 delivery ( QO2 )-to-O2 utilization ( VO2 ) matching and vascular control that might help to explain poor exercise tolerance in PH. Furthermore, we investigated the peripheral effects of nitric oxide (NO) in attenuating these decrements. Male Sprague-Dawley rats (n = 21) were administered monocrotaline (MCT; 50 mg/kg, i.p.) to induce PH. Disease progression was monitored via echocardiography. Phosphorescence quenching determined the O2 partial pressure in the interstitial space ( PO2is ) in the spinotrapezius muscle at rest and during contractions under control (SNP-) and NO-donor (sodium nitroprusside, SNP+) conditions. MCT rats displayed right ventricular (RV) hypertrophy (right ventricle/(left ventricle + septum): 0.44 (0.13) vs. 0.28 (0.05)), pulmonary congestion, increased RV systolic pressure (48 (18) vs. 20 (8) mmHg) and arterial hypoxaemia ( PaO2 : 64 (9) vs. 82 (9) mmHg) compared to healthy controls (HC) (P

Spanish Ministry of Economy and Competitiveness, Grant/Award Number: DEP2013--47540, DEP2016-79512--R and DEP2017--91544--EXP; Spanish Ministry of Economy, Industry and Competitiveness (MINECO); European Regional Development Fund (FEDER), Grant/Award Number: RYC--2016--21199 and ENDORE SAF2017--87526--R; Junta de Andalucia, Grant/Award Number: BIO--302 and US--1254251; University of Jaen, Grant/Award Number: PAIUJA--EI_CTS02; Spanish Ministry of Education, Culture and Sport, Grant/Award Number: FPU 16/02760; NIH, Grant/Award Number:UO1 TR002004; PERC Systems Biology Fund; Unit of Excellence on EXERNET Research Network on Exercise and Health in Special Populations; Alicia Koplowitz Foundation; Henning Och Johan Throne--Holsts Stiftelse Grant; University of Granada, Plan Propio de Investigacion 2016, Excellence actions: Units of Excellence; Unit of Excellence on Exercise and Health (UCEES); Junta de Andalucia, Consejeria de Conocimiento, Investigacion y Universidades and European Regional Development Fund (ERDF), Grant/Award Number: SOMM17/6107/UGR; European Regional Development Funds, Grant/Award Number: B--CTS-355--UGR18 and B--CTS--500--UGR18; Funding for open access charge: Universidad de Granada/CBUA, Objectives: High cardiorespiratory fitness (CRF) levels reduce the risk of developing cardiovascular disease (CVD) during adulthood. However, little is known about the molecular mechanisms underlying the health benefits of high CRF levels at the early stage of life. This study aimed to analyze the whole-blood transcriptome profile of fit children with overweight/obesity (OW/OB) compared to unfit children with OW/OB. Design: 27 children with OW/OB (10.14 ± 1.3 years, 59% boys) from the ActiveBrains project were evaluated. VO2peak was assessed using a gas analyzer, and participants were categorized into fit or unfit according to the CVD risk-related cut-points. Whole-blood transcriptome profile (RNA sequencing) was analyzed. Differential gene expression analysis was performed using the limma R/Bioconductor software package (analyses adjusted by sex and maturational status), and pathways’ enrichment analysis was performed with DAVID. In addition, in silico validation data mining was performed using the PHENOPEDIA database. Results: 256 genes were differentially expressed in fit children with OW/OB compared to unfit children with OW/OB after adjusting by sex and maturational status (FDR < 0.05). Enriched pathway analysis identified gene pathways related to inflammation (eg, dopaminergic and GABAergic synapse pathways). Interestingly, in silico validation data mining detected a set of the differentially expressed genes to be related to CVD, metabolic syndrome, hypertension, inflammation, and asthma. Conclusion: The distinct pattern of whole-blood gene expression in fit children with OW/OB reveals genes and gene pathways that might play a role in reducing CVD risk factors later in life., Spanish Ministry of Economy and Competitiveness DEP2013-47540 DEP2016-79512-R DEP2017-91544-EXP, Spanish Ministry of Economy, Industry and Competitiveness (MINECO), European Commission RYC-2016-21199, ENDORE SAF2017-87526-R, Junta de Andalucia BIO-302 US-1254251, University of Jaen PAIUJA-EI_CTS02, Spanish Ministry of Education, Culture and Sport FPU 16/02760, United States Department of Health & Human Services, National Institutes of Health (NIH) - USA UO1 TR002004, PERC Systems Biology Fund, Unit of Excellence on EXERNET Research Network on Exercise and Health in Special Populations, Alicia Koplowitz Foundation, Henning Och Johan Throne-Holsts Stiftelse Grant, University of Granada, Unit of Excellence on Exercise and Health (UCEES), Junta de Andalucia, Consejeria de Conocimiento, Investigacion y Universidades and European Regional, Development Fund (ERDF) SOMM17/6107/UGR European Commission B-CTS-355-UGR18 B-CTS-500-UGR18, Universidad de Granada/CBUA

Adverse fetal environment, in particular a shortage or excess of nutrients, is associated with increased risks of metabolic diseases later in life. However, the molecular mechanisms underlying this developmental origin of adult diseases remain unclear. Here, we directly tested the role of mitochondrial stress in mediating fetal programming in mice by enzymatically depleting mtDNA in zygotes. mtDNA-targeted plasmid microinjection is used to reduce embryonic mtDNA copy number directly, followed by embryo transfer. Mice with reduced zygote mtDNA copy number were born morphologically normal and showed no accelerated body weight gain. However, at 5 months of age these mice showed markedly increased hepatic lipidosis and became glucose-intolerant. Hepatic mRNA and protein expressions of peroxisome proliferator-activated receptor α (Pparα), a key transcriptional regulator of lipid metabolism, were significantly decreased as a result of increased DNA methylation in its proximal regulatory region. These results indicate that perturbation of mitochondrial function around the periconceptional period causes hypermethylation and thus suppressed expression of PPARα in fetal liver, leading to impaired hepatic lipid metabolism. Our findings provide the first direct evidence that mitochondrial stress mediates epigenetic changes associated with fetal programming of adult diseases in a mammalian system.