Capillary oxygen regulates demand-supply coupling by triggering connexin40-mediated conduction: Rethinking the metabolic hypothesis.

Coupling red blood cell (RBC) supply to O2 demand is an intricate process requiring O2 sensing, generation of a stimulus, and signal transduction that alters upstream arteriolar tone. Although actively debated, this process has been theorized to be induced by hypoxia and to involve activation of endothelial inwardly rectifying K+ channels (KIR) 2.1 by elevated extracellular K+ to trigger conducted hyperpolarization via connexin40 (Cx40) gap junctions to upstream resistors. This concept was tested in resting healthy skeletal muscle of Cx40-/- and endothelial KIR2.1-/- mice using state-of-the-art live animal imaging where the local tissue O2 environment was manipulated using a custom gas chamber. Second-by-second capillary RBC flow responses were recorded as O2 was altered. A stepwise drop in PO2 at the muscle surface increased RBC supply in capillaries of control animals while elevated O2 elicited the opposite response; capillaries were confirmed to express Cx40. The RBC flow responses were rapid and tightly coupled to O2; computer simulations did not support hypoxia as a driving factor. In contrast, RBC flow responses were significantly diminished in Cx40-/- mice. Endothelial KIR2.1-/- mice, on the other hand, reacted normally to O2 changes, even when the O2 challenge was targeted to a smaller area of tissue with fewer capillaries. Conclusively, microvascular O2 responses depend on coordinated electrical signaling via Cx40 gap junctions, and endothelial KIR2.1 channels do not initiate the event. These findings reconceptualize the paradigm of blood flow regulation in skeletal muscle and how O2 triggers this process in capillaries independent of extracellular K+.

Association between placental oxygen transport and fetal brain cortical development: a study in monochorionic diamniotic twins.

Normal cortical growth and the resulting folding patterns are crucial for normal brain function. Although cortical development is largely influenced by genetic factors, environmental factors in fetal life can modify the gene expression associated with brain development. As the placenta plays a vital role in shaping the fetal environment, affecting fetal growth through the exchange of oxygen and nutrients, placental oxygen transport might be one of the environmental factors that also affect early human cortical growth. In this study, we aimed to assess the placental oxygen transport during maternal hyperoxia and its impact on fetal brain development using MRI in identical twins to control for genetic and maternal factors. We enrolled 9 pregnant subjects with monochorionic diamniotic twins (30.03 ± 2.39 gestational weeks [mean ± SD]). We observed that the fetuses with slower placental oxygen delivery had reduced volumetric and surface growth of the cerebral cortex. Moreover, when the difference between placenta oxygen delivery increased between the twin pairs, sulcal folding patterns were more divergent. Thus, there is a significant relationship between placental oxygen transport and fetal brain cortical growth and folding in monochorionic twins.

Integrated modeling and simulation of recruitment of myocardial perfusion and oxygen delivery in exercise.

While exercise-mediated vasoregulation in the myocardium is understood to be governed by autonomic, myogenic, and metabolic-mediated mechanisms, we do not yet understand the spatial heterogeneity of vasodilation or its effects on microvascular flow patterns and oxygen delivery. This study uses a simulation and modeling approach to explore the mechanisms underlying the recruitment of myocardial perfusion and oxygen delivery in exercise. The simulation approach integrates model components representing: whole-body cardiovascular hemodynamics, cardiac mechanics and myocardial work; myocardial perfusion; and myocardial oxygen transport. Integrating these systems together, model simulations reveal: (1.) To match expected flow and transmural flow ratios at increasing levels of exercise, a greater degree of vasodilation must occur in the subendocardium compared to the subepicardium. (2.) Oxygen extraction and venous oxygenation are predicted to substantially decrease with increasing exercise level preferentially in the subendocardium, suggesting that an oxygen-dependent error signal driving metabolic mediated recruitment of flow would be operative only in the subendocardium. (3.) Under baseline physiological conditions approximately 4% of the oxygen delivered to the subendocardium may be supplied via retrograde flow from coronary veins.

Endurance exercise training changes the limitation on muscle V ̇ O 2 max ${\dot{V}}_{{{\mathrm{O}}}_{\mathrm{2}}{\mathrm{max}}}$ in normoxia from the capacity to utilize O2 to the capacity to transport O2.

Maximal oxygen (O2 ) uptake ( V ̇ O 2 max ${\dot{V}}_{{{\mathrm{O}}}_{\mathrm{2}}{\mathrm{max}}}$ ) is an important parameter with utility in health and disease. However, the relative importance of O2 transport and utilization capacities in limiting muscle V ̇ O 2 max ${\dot{V}}_{{{\mathrm{O}}}_{\mathrm{2}}{\mathrm{max}}}$ before and after endurance exercise training is not well understood. Therefore, the present study aimed to identify the mechanisms determining muscle V ̇ O 2 max ${\dot{V}}_{{{\mathrm{O}}}_{\mathrm{2}}{\mathrm{max}}}$ pre- and post-endurance exercise training in initially sedentary participants. In five initially sedentary young males, radial arterial and femoral venous P O 2 ${P}_{{{\mathrm{O}}}_{\mathrm{2}}}$ (blood samples), leg blood flow (thermodilution), and myoglobin (Mb) desaturation (1 H nuclear magnetic resonance spectroscopy) were measured during maximal single-leg knee-extensor exercise (KE) breathing either 12%, 21% or 100% O2 both pre and post 8 weeks of KE training (1 h, 3 times per week). Mb desaturation was converted to intracellular P O 2 ${P}_{{{\mathrm{O}}}_{\mathrm{2}}}$ using an O2  half-saturation pressure of 3.2 mmHg. Pre-training muscle V ̇ O 2 max ${\dot{V}}_{{{\mathrm{O}}}_{\mathrm{2}}{\mathrm{max}}}$ was not significantly different across inspired O2 conditions (12%: 0.47 ± 0.10; 21%: 0.52 ± 0.13; 100%: 0.54 ± 0.01 L min-1 , all q > 0.174), despite significantly greater muscle mean capillary-intracellular P O 2 ${P}_{{{\mathrm{O}}}_{\mathrm{2}}}$ gradients in normoxia (34 ± 3 mmHg) and hyperoxia (40 ± 7 mmHg) than hypoxia (29 ± 5 mmHg, both q < 0.024). Post-training muscle V ̇ O 2 max ${\dot{V}}_{{{\mathrm{O}}}_{\mathrm{2}}{\mathrm{max}}}$ was significantly different across all inspired O2 conditions (12%: 0.59 ± 0.11; 21%: 0.68 ± 0.11; 100%: 0.76 ± 0.09 mmHg, all q < 0.035), as were the muscle mean capillary-intracellular P O 2 ${P}_{{{\mathrm{O}}}_{\mathrm{2}}}$ gradients (12%: 32 ± 2; 21%: 37 ± 2; 100%: 45 ± 7 mmHg, all q < 0.029). In these initially sedentary participants, endurance exercise training changed the basis of limitation on muscle V ̇ O 2 max ${\dot{V}}_{{{\mathrm{O}}}_{\mathrm{2}}{\mathrm{max}}}$ in normoxia from the mitochondrial capacity to utilize O2 to the capacity to transport O2 to the mitochondria. KEY POINTS: Maximal O2 uptake is an important parameter with utility in health and disease. The relative importance of O2 transport and utilization capacities in limiting muscle maximal O2 uptake before and after endurance exercise training is not well understood. We combined the direct measurement of active muscle maximal O2 uptake with the measurement of muscle intracellular P O 2 ${P}_{{{\mathrm{O}}}_{\mathrm{2}}}$ before and after 8 weeks of endurance exercise training. We show that increasing O2 availability did not increase muscle maximal O2 uptake before training, whereas increasing O2 availability did increase muscle maximal O2 uptake after training. The results suggest that, in these initially sedentary participants, endurance exercise training changed the basis of limitation on muscle maximal O2 uptake in normoxia from the mitochondrial capacity to utilize O2 to the capacity to transport O2 to the mitochondria.

Modeling cerebrovascular responses to assess the impact of the collateral circulation following middle cerebral artery occlusion.

OBJECTIVE: An improved understanding of the role of the leptomeningeal collateral circulation in blood flow compensation following middle cerebral artery (MCA) occlusion can contribute to more effective treatment development for ischemic stroke. The present study introduces a model of the cerebral circulation to predict cerebral blood flow and tissue oxygenation following MCA occlusion. METHODS: The model incorporates flow regulation mechanisms based on changes in pressure, shear stress, and metabolic demand. Oxygen saturation in cerebral vessels and tissue is calculated using a Krogh cylinder model. The model is used to assess the effects of changes in oxygen demand and arterial pressure on cerebral blood flow and oxygenation after MCA occlusion. RESULTS: An increase from five to 11 leptomeningeal collateral vessels was shown to increase the oxygen saturation in the region distal to the occlusion by nearly 100%. Post-occlusion, the model also predicted a loss of autoregulation and a decrease in flow to the ischemic territory as oxygen demand was increased; these results were consistent with data from experiments that induced cerebral ischemia. CONCLUSIONS: This study highlights the importance of leptomeningeal collaterals following MCA occlusion and reinforces the idea that lower oxygen demand and higher arterial pressure improve conditions of flow and oxygenation.

Boosting Bulk Oxygen Transport with Accessible Electrode Nanostructure in Low Pt Loading PEMFCs.

Despite the high potential for reducing carbon emissions and contributing to the future of energy utilization, polymer electrolyte membrane fuel cells (PEMFCs) face challenges such as high costs and sluggish oxygen transport in cathode catalyst layers (CCLs). In this study, the impact of pore size distribution on bulk oxygen transport behavior is explored by introducing nano calcium carbonate of varying particle sizes for pore-forming. Physicochemical characterizations for are employed to examine the electrode structure, while in situ electrochemical measurements are used to scrutinize bulk oxygen transport resistance, effective oxygen diffusivity ( D O 2 eff $D_{{{\mathrm{O}}}_2}^{{\mathrm{eff}}}$ ) and fuel cell performance. Additionally, the CCLs are constructed with aid of Lattice Boltzmann method (LBM) simulations and D O 2 eff $D_{{{\mathrm{O}}}_2}^{{\mathrm{eff}}}$ for CCLs with different pore size distribution are calculated. The findings reveal that D O 2 eff $D_{{{\mathrm{O}}}_2}^{{\mathrm{eff}}}$ initially increases and then decreases as the most probable pore size increases. A "sphere-pipe" model is proposed to describe practical bulk oxygen transport in CCLs, highlighting the significant role of not only the pore size of secondary pores but also the number of primary pores in bulk oxygen transport.

Pulmonary hypertension impairs vasomotor function in rat diaphragm arterioles.

Pulmonary hypertension (PH) is a chronic, progressive condition in which respiratory muscle dysfunction is a primary contributor to exercise intolerance and dyspnea in patients. Contractile function, blood flow distribution, and the hyperemic response are altered in the diaphragm with PH, and we sought to determine whether this may be attributed, in part, to impaired vasoreactivity of the resistance vasculature. We hypothesized that there would be blunted endothelium-dependent vasodilation and impaired myogenic responsiveness in arterioles from the diaphragm of PH rats. Female Sprague-Dawley rats were randomized into healthy control (HC, n = 9) and monocrotaline-induced PH rats (MCT, n = 9). Endothelium-dependent and -independent vasodilation and myogenic responses were assessed in first-order arterioles (1As) from the medial costal diaphragm in vitro. There was a significant reduction in endothelium-dependent (via acetylcholine; HC, 78 ± 15% vs. MCT, 47 ± 17%; P < 0.05) and -independent (via sodium nitroprusside; HC, 89 ± 10% vs. MCT, 66 ± 10%; P < 0.05) vasodilation in 1As from MCT rats. MCT-induced PH also diminished myogenic constriction (P < 0.05) but did not alter passive pressure responses. The diaphragmatic weakness, impaired hyperemia, and blood flow redistribution associated with PH may be due, in part, to diaphragm vascular dysfunction and thus compromised oxygen delivery which occurs through both endothelium-dependent and -independent mechanisms.

Nanomaterial-related hemoglobin-based oxygen carriers, with emphasis on liposome and nano-capsules, for biomedical applications: current status and future perspectives.

Oxygen is necessary for life and plays a key pivotal in maintaining normal physiological functions and treat of diseases. Hemoglobin-based oxygen carriers (HBOCs) have been studied and developed as a replacement for red blood cells (RBCs) in oxygen transport due to their similar oxygen-carrying capacities. However, applications of HBOCs are hindered by vasoactivity, oxidative toxicity, and a relatively short circulatory half-life. With advancements in nanotechnology, Hb encapsulation, absorption, bioconjugation, entrapment, and attachment to nanomaterials have been used to prepare nanomaterial-related HBOCs to address these challenges and pend their application in several biomedical and therapeutic contexts. This review focuses on the progress of this class of nanomaterial-related HBOCs in the fields of hemorrhagic shock, ischemic stroke, cancer, and wound healing, and speculates on future research directions. The advancements in nanomaterial-related HBOCs are expected to lead significant breakthroughs in blood substitutes, enabling their widespread use in the treatment of clinical diseases.

Failing with Cyanosis-Heart Failure in End-Stage Unrepaired or Partially Palliated Congenital Heart Disease.

Heart failure in cyanotic congenital heart disease (CHD) is diagnosed clinically rather than relying solely on ventricular function assessments. Patients with cyanosis often present with clinical features indicative of heart failure. Although myocardial injury and dysfunction likely contribute to cyanotic CHD, the primary concern is the reduced delivery of oxygen to tissues. Symptoms such as fatigue, lassitude, dyspnea, headaches, myalgias, and a cold sensation underscore inadequate tissue oxygen delivery, forming the basis for defining heart failure in cyanotic CHD. Thus, it is pertinent to delve into the components of oxygen delivery in this context.

Fixing skeletal muscle PO2 eliminates hyperinsulinemic microvascular blood flow response.

OBJECTIVE: To determine if insulin-mediated hyperemia is partially dependent on local muscle oxygen concentration. METHODS: Sprague-Dawley rats were anesthetized, and the extensor digitorum longus (EDL) was reflected onto an inverted microscope. Intravital video microscopy sequences were recorded during baseline and hyperinsulinemic euglycemia. The muscle was reflected over a glass stage insert (Experiment 1a and 1b), or over a gas exchange chamber (Experiment 2), and microvascular capillary blood flow was recorded during sequential changes (7%-12%-2%-7%) of oxygen (O2 ) concentration. Blood flow was measured by the red blood cell supply rate (SR) in number of cells per second. All animal protocols were approved by Memorial University's Institutional Animal Care Committee. RESULTS: In Experiment 1a, SR increased from 8.0 to 14.0 cells/s at baseline to euglycemia (p = .01), while no significant SR variation was detected after performing a sham hyperinsulinemic euglycemic clamp (Experiment 1b). In Experiment 2, SR decreased at 12% O2 and increased at 2% O2 , compared to 7% O2 , under both experimental conditions. Magnitude of SR responses to oxygen oscillations during euglycemia were not different to those at baseline at each O2 concentration (p > .9). CONCLUSIONS: Our results suggest that increased blood flow observed in response to insulin is eliminated if tissue oxygen microenvironment is fixed at a given oxygen concentration.

Aqp5-/- mice exhibit reduced maximal body O2 consumption under cold exposure, normal pulmonary gas exchange, and impaired formation of brown adipose tissue.

The fundamental body functions that determine maximal O2 uptake (V̇o2max) have not been studied in Aqp5-/- mice (aquaporin 5, AQP5). We measured V̇o2max to globally assess these functions and then investigated why it was found altered in Aqp5-/- mice. V̇o2max was measured by the Helox technique, which elicits maximal metabolic rate by intense cold exposure of the animals. We found V̇o2max reduced in Aqp5-/- mice by 20%-30% compared with wild-type (WT) mice. As AQP5 has been implicated to act as a membrane channel for respiratory gases, we studied whether this is caused by the known lack of AQP5 in the alveolar epithelial membranes of Aqp5-/- mice. Lung function parameters as well as arterial O2 saturation were normal and identical between Aqp5-/- and WT mice, indicating that AQP5 does not contribute to pulmonary O2 exchange. The cause for the decreased V̇o2max thus might be found in decreased O2 consumption of an intensely O2-consuming peripheral organ such as activated brown adipose tissue (BAT). We found indeed that absence of AQP5 greatly reduces the amount of interscapular BAT formed in response to 4 wk of cold exposure, from 63% in WT to 25% in Aqp5-/- animals. We conclude that lack of AQP5 does not affect pulmonary O2 exchange, but greatly inhibits transformation of white to brown adipose tissue. As under cold exposure, BAT is a major source of the animals' heat production, reduction of BAT likely causes the decrease in V̇o2max under this condition.

Oxygen transport across tank-treading red blood cell: Individual and joint roles of flow convection and oxygen-hemoglobin reaction.

Gas, especially oxygen, transport in the microcirculation is a complex phenomenon, however, of critical importance for maintaining normal biological functions, and the cytoplasm fluid in red blood cells (RBCs) is the major vehicle for transporting oxygen from lungs to tissues via the circulatory system. Existing theoretical and numerical studies have neglected the cytoplasm convection effect by treating RBCs as rigid particles undergoing a constant translation velocity. As a consequence, the influence and mechanism of the cytoplasm flow on oxygen transport are still not clear in microcirculation research. In this study, we consider a tank-treading capsule in shear flow, which is generated with two parallel plates moving in opposite directions: the top plate of a higher oxygen pressure (PO2) representing the RBC core in the central region of a microvessel and the bottom plate of a lower PO2 representing the microvessel wall. Numerical simulations are conducted to investigate the individual and combined effects of cytoplasm convection and oxygen-hemoglobin (O2-Hb) reaction on the oxygen transport efficiency across the tank-treading capsule, and different PO2 situations and shear rates are also tested. Due to the lower oxygen diffusivity in cytoplasm, the presence of the capsule reduces the oxygen transfer flux across the gap by 7.34 % in the pure diffusion system where the flow convection and O2-Hb reaction are both neglected. Including the flow convection or the O2-Hb reaction has little influence on the oxygen flux; however, when they act together as in real microcirculation situations, the enhancement in oxygen transport could be significant, especially in the low PO2 and high shear rate situations. In particular, with the respective PO2 at 60 and 30 mmHg on the top and bottom plates and a 400 s-1 shear rate, the oxygen flux reduction is only 0.02 %, suggesting that the cytoplasm convection can improve the oxygen transport across RBCs considerably. The simulation results are scrutinized to explore the underlying mechanism for the enhancement, and a new nondimensional parameter is introduced to characterize the importance of cytoplasm convection in oxygen transport. These simulation results, discussion and analysis could be helpful for a better understanding of the complex oxygen transport process and therefor valuable for relevant studies.

Determinants of maximal oxygen consumption.

This article lays out the determinants of maximal O2 consumption (VO2max) achieved during high intensity endurance exercise. It is not a traditional topical review but rather an educational essay that intertwines chance observations made during an unrelated research project with a subsequent program of stepwise thought, analysis and experimentation to reveal how O2 is delivered to and used by the mitochondria. The centerpiece is the recognition that O2 is delivered by an inter-dependent system of transport components functioning as a "bucket brigade", made up of the lungs, heart, blood and circulation, and the muscles themselves, each of which affects O2 transport by similar amounts as they change. There is thus no single "limiting factor" to VO2max. Moreover, each component is shown to quantitatively affect the performance of the others. Mitochondrial respiration is integrated into the O2 transport system analysis to reveal its separate contribution to VO2max, and to show that mitochondrial PO2 at VO2max must be extremely low. Clinical application of the O2 transport systems analysis is described to separate central cardiopulmonary from peripheral tissue contributions to exercise limitation, illustrated by a study of patients with COPD. Finally, a short discussion of why muscles operating maximally must endure an almost anoxic state is offered. The hope is that in sum, both the increased understanding of O2 transport and the scientific approach to achieving that understanding described in the review can serve as a model for solving other complex problems going forward.

Propagation of an idealized infection in an airway tree, consequences of the inflammation on the oxygen transfer to blood.

A mathematical model of infection, inflammation and immune response in an idealized bronchial tree is developed. This work is based on a model from the literature that is extended to account for the propagation dynamics of an infection between the airways. The inflammation affects the size of the airways, the air flows distribution in the airway tree, and, consequently, the oxygen transfers to blood. We test different infections outcomes and propagation speed. In the hypotheses of our model, the inflammation can reduce notably and sometimes drastically the oxygen flow to blood. Our model predicts how the air flows and oxygen exchanges reorganize in the tree during an infection. Our results highlight the links between the localization of the infection and the amplitude of the loss of oxygen flow to blood. We show that a compensation phenomena due to the reorganization of the flow exists, but that it remains marginal unless the power produced the ventilation muscles is increased. Our model forms a first step towards a better understanding of the dynamics of bronchial infections.

Engineering Escherichia coli for efficient assembly of heme proteins.

BACKGROUND: Heme proteins, such as hemoglobin, horseradish peroxidase and cytochrome P450 (CYP) enzyme, are highly versatile and have widespread applications in the fields of food, healthcare, medical and biological analysis. As a cofactor, heme availability plays a pivotal role in proper folding and function of heme proteins. However, the functional production of heme proteins is usually challenging mainly due to the insufficient supply of intracellular heme. RESULTS: Here, a versatile high-heme-producing Escherichia coli chassis was constructed for the efficient production of various high-value heme proteins. Initially, a heme-producing Komagataella phaffii strain was developed by reinforcing the C4 pathway-based heme synthetic route. Nevertheless, the analytical results revealed that most of the red compounds generated by the engineered K. phaffii strain were intermediates of heme synthesis which were unable to activate heme proteins. Subsequently, E. coli strain was selected as the host to develop heme-producing chassis. To fine-tune the C5 pathway-based heme synthetic route in E. coli, fifty-two recombinant strains harboring different combinations of heme synthesis genes were constructed. A high-heme-producing mutant Ec-M13 was obtained with negligible accumulation of intermediates. Then, the functional expression of three types of heme proteins including one dye-decolorizing peroxidase (Dyp), six oxygen-transport proteins (hemoglobin, myoglobin and leghemoglobin) and three CYP153A subfamily CYP enzymes was evaluated in Ec-M13. As expected, the assembly efficiencies of heme-bound Dyp and oxygen-transport proteins expressed in Ec-M13 were increased by 42.3-107.0% compared to those expressed in wild-type strain. The activities of Dyp and CYP enzymes were also significantly improved when expressed in Ec-M13. Finally, the whole-cell biocatalysts harboring three CYP enzymes were employed for nonanedioic acid production. High supply of intracellular heme could enhance the nonanedioic acid production by 1.8- to 6.5-fold. CONCLUSION: High intracellular heme production was achieved in engineered E. coli without significant accumulation of heme synthesis intermediates. Functional expression of Dyp, hemoglobin, myoglobin, leghemoglobin and CYP enzymes was confirmed. Enhanced assembly efficiencies and activities of these heme proteins were observed. This work provides valuable guidance for constructing high-heme-producing cell factories. The developed mutant Ec-M13 could be employed as a versatile platform for the functional production of difficult-to-express heme proteins.

Simulation of Angiogenesis in Three Dimensions: Development of the Retinal Circulation.

A theoretical model is used to describe the three-dimensional development of the retinal circulation in the human eye, which occurs after the initial spread of vasculature across the inner surface of the retina. In the model, random sprouting angiogenesis is driven by a growth factor that is produced in tissue at a rate dependent on oxygen level and diffuses to existing vessels. Vessel sprouts connect to form pathways for blood flow and undergo remodeling and pruning. These processes are controlled by known or hypothesized vascular responses to hemodynamic and biochemical stimuli, including conducted responses along vessel walls. The model shows regression of arterio-venous connections on the surface of the retina, allowing perfusion of the underlying tissue. A striking feature of the retinal circulation is the formation of two vascular plexuses located at the inner and outer surfaces of the inner nuclear layer within the retina. The model is used to test hypotheses regarding the formation of these structures. A mechanism based on local production and diffusion of growth factor is shown to be ineffective. However, sprout guidance by localized structures on the boundaries of the inner nuclear layer can account for plexus formation. The resulting networks have vascular density, perfusion and oxygen transport characteristics consistent with observed properties. The model shows how stochastic generation of vascular sprouts combined with a set of biologically based response mechanisms can lead to the generation of a specialized three-dimensional vascular structure with a high degree of organization.

Tissue Oxygenation Around Capillaries: Effects of Hematocrit and Arteriole Oxygen Condition.

Oxygen transfer in the microvasculature is a complex phenomenon that involves multiple physical and chemical processes and multiple media. Hematocrit, the volume fraction of red blood cells (RBCs) in blood, has direct influences on the blood flow as well as the oxygen supply in the microcirculation. On the one hand, a higher hematocrit means that more RBCs present in capillaries, and thus, more oxygen is available at the source end. On the other hand, the flow resistance increases with hematocrit, and therefore, the RBC motion becomes slower, which in turn reduces the influx of oxygen-rich RBCs entering capillaries. Such double roles of hematocrit have not been investigated adequately. Moreover, the oxygen-hemoglobin dissociation rate depends on the oxygen tension and hemoglobin saturation of the cytoplasm inside RBCs, and the dissociation kinetics exhibits a nonlinear fashion at different oxygen tensions. To understand how these factors and mechanisms interplay in the oxygen transport process, computational modeling and simulations are favorite since we have a good control of the system parameters and also we can access to the detailed information during the transport process. In this study, we conduct numerical simulations for the blood flow and RBC deformation along a capillary and the oxygen transfer from RBCs to the surrounding tissue. Different values for the hematocrit, arteriole oxygen tension, tissue metabolism rate and hemoglobin concentration and affinity are considered, and the simulated spatial and temporal variations of oxygen concentration are analyzed in conjunction with the nonlinear oxygen-hemoglobin reaction kinetics. Our results show that there are two competing mechanisms for the tissue oxygenation response to a hematocrit increases: the favorite effect of the higher RBC density and the negative effect of the slower RBC motion. Moreover, in the low oxygen situations with RBC oxygen tension less than 50 mmHg at capillary inlet, the reduced RBC velocity effect dominates, resulting in a decrease in tissue oxygenation at higher hematocrit. On the opposite, for RBC oxygen tension higher than 50 mmHg when entering the capillary, a higher hematocrit is beneficial to the tissue oxygenation. More interestingly, the pivoting arteriole oxygen tension at which the two competing mechanisms switch dominance on tissue oxygenation becomes lower for higher oxygen-hemoglobin affinity and lower hemoglobin concentration. This observation has also been analyzed based on the oxygen supply from RBCs and the oxygen-hemoglobin reaction kinetics. The results and discussions presented in this article could be helpful for a better understanding of oxygen transport in microcirculation.

Low myoglobin concentration in skeletal muscle of elite cyclists is associated with low mRNA expression levels.

Myoglobin is essential for oxygen transport to the muscle fibers. However, measurements of myoglobin (Mb) protein concentrations within individual human muscle fibers are scarce. Recent observations have revealed surprisingly low Mb concentrations in elite cyclists, however it remains unclear whether this relates to Mb translation, transcription and/or myonuclear content. The aim was to compare Mb concentration, Mb messenger RNA (mRNA) expression levels and myonuclear content within muscle fibers of these elite cyclists with those of physically-active controls. Muscle biopsies were obtained from m. vastus lateralis in 29 cyclists and 20 physically-active subjects. Mb concentration was determined by peroxidase staining for both type I and type II fibers, Mb mRNA expression level was determined by quantitative PCR and myonuclear domain size (MDS) was obtained by immunofluorescence staining. Average Mb concentrations (mean ± SD: 0.38 ± 0.04 mM vs. 0.48 ± 0.19 mM; P = 0.014) and Mb mRNA expression levels (0.067 ± 0.019 vs. 0.088 ± 0.027; P = 0.002) were lower in cyclists compared to controls. In contrast, MDS and total RNA per mg muscle were not different between groups. Interestingly, in cyclists compared to controls, Mb concentration was only lower for type I fibers (P < 0.001), but not for type II fibers (P > 0.05). In conclusion, the lower Mb concentration in muscle fibers of elite cyclists is partly explained by lower Mb mRNA expression levels per myonucleus and not by a lower myonuclear content. It remains to be determined whether cyclists may benefit from strategies that upregulate Mb mRNA expression levels, particularly in type I fibers, to enhance their oxygen supply.

The Significance of Lipids for the Absorption and Release of Oxygen in Biological Organisms.

A critically important step for the uptake and transport of oxygen (O2) in living organisms is the crossing of the phase boundary between gas (or water) and lipid/proteins in the cell. Classically, this transport across the phase boundary is explained as a transport by proteins or protein-based structures. In our contribution here, we want to show the significance of passive transport of O2 also (and in some cases probably predominantly) through lipids in many if not all aerobic organisms. In plants, the significance of lipids for gas exchange (absorption of CO2 and release of O2) is well recognized. The leaves of plants have a cuticle layer as the last film on both sides formed by polyesters and lipids. In animals, the skin has sebum as its last layer consisting of a mixture of neutral fatty esters, cholesterol and waxes which are also at the border between the cells of the body and the air. The last cellular layers of skin are not vascularized therefore their metabolism totally depends on this extravasal O2 absorption, which cannot be replenished by the bloodstream. The human body absorbs about 0.5% of O2 through the skin. In the brain, myelin, surrounding nerve cell axons and being formed by oligodendrocytes, is most probably also responsible for enabling O2 transport from the extracellular space to the cells (neurons). Myelin, being not vascularized and consisting of water, lipids and proteins, seems to absorb O2 in order to transport it to the nerve cell axon as well as to perform extramitochondrial oxidative phosphorylation inside the myelin structure around the axons (i.e., myelin synthesizes ATP) - similarly to the metabolic process occurring in concentric multilamellar structures of cyanobacteria. Another example is the gas transport in the lung where lipids play a crucial role in the surfactant ensuring incorporation of O2 in the alveoli where there are lamellar body and tubular myelin which form multilayered surface films at the air-membrane border of the alveolus. According to our view, the role played by lipids in the physical absorption of gases appears to be crucial to the existence of many, if not all, of the living aerobic species.

The oxygen transport cascade and exercise: Lessons from comparative physiology.

Studies of animal physiology not only provide valuable knowledge for the species in question, but also offer insights into human physiology. This thought is best highlighted by the 'Krogh Principle', which states "for many problems there is an animal on which it can be most conveniently studied". This graphical review focuses on three distinct stages of the oxygen transport cascade in which human exercise physiology knowledge has been enhanced by studies carried out in animal models. We begin by exploring ventilation, and the detrimental effects of cold, dry air on the airways in two sets of elite athletes, the cross-country skier and the racing sled dog. We then discuss the transport of oxygen via hemoglobin in humans and deer mice with relatively shifted oxygen dissociation curves. Finally, we consider the technical difficulties of measuring respiratory muscle blood flow in exercising humans and how an equine model can provide an understanding of the distribution of blood flow during exercise. These cases illustrate the complementary nature of physiological studies across species.