Edited by: Anna Bogdanova, University of Zurich, Switzerland
Reviewed by: Giovanni Lombardi, I.R.C.C.S. Galeazzi Scientific Institute, Italy; Philippe Connes, UMR Inserm 665 Red Blood Cell Integrative Biology, Guadeloupe
*Correspondence: Heimo Mairbäurl, Medical Clinic VII, Sports Medicine, University of Heidelberg, INF 410, 69120 Heidelberg, Germany e-mail:
This article was submitted to Membrane Physiology and Membrane Biophysics, a section of the journal Frontiers in Physiology.
This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
During exercise the cardiovascular system has to warrant substrate supply to working muscle. The main function of red blood cells in exercise is the transport of O2 from the lungs to the tissues and the delivery of metabolically produced CO2 to the lungs for expiration. Hemoglobin also contributes to the blood's buffering capacity, and ATP and NO release from red blood cells contributes to vasodilation and improved blood flow to working muscle. These functions require adequate amounts of red blood cells in circulation. Trained athletes, particularly in endurance sports, have a decreased hematocrit, which is sometimes called “sports anemia.” This is not anemia in a clinical sense, because athletes have in fact an increased total mass of red blood cells and hemoglobin in circulation relative to sedentary individuals. The slight decrease in hematocrit by training is brought about by an increased plasma volume (PV). The mechanisms that increase total red blood cell mass by training are not understood fully. Despite stimulated erythropoiesis, exercise can decrease the red blood cell mass by intravascular hemolysis mainly of senescent red blood cells, which is caused by mechanical rupture when red blood cells pass through capillaries in contracting muscles, and by compression of red cells e.g., in foot soles during running or in hand palms in weightlifters. Together, these adjustments cause a decrease in the average age of the population of circulating red blood cells in trained athletes. These younger red cells are characterized by improved oxygen release and deformability, both of which also improve tissue oxygen supply during exercise.
The primary role of red blood cells is the transport of respiratory gasses. In the lung, oxygen (O2) diffuses across the alveolar barrier from inspired air into blood, where the majority is bound by hemoglobin (Hb) to form oxy-Hb, a process called oxygenation. Hb is contained in the red blood cells, which, being circulated by the cardiovascular system, deliver O2 to the periphery where it is released from its Hb-bond (deoxygenation) and diffuses into the cells. While passing peripheral capillaries, carbon dioxide (CO2) produced by the cells reaches the red blood cells, where carbonic anhydrase (CA) in tissues and red blood cells converts a large portion of CO2 into bicarbonate (HCO−3). CO2 is also bound by Hb, preferentially by deoxygenated Hb forming carboxy-bonds. Both forms of CO2 are delivered to the lung, where CA converts HCO−3 back into CO2. CO2 is also released from its bond to Hb and diffuses across the alveolar wall to be expired.
The biological significance of O2 transport by Hb is well-illustrated by anemia where decreased Hb also decreases exercise performance despite a compensatory increase in cardiac output (Ledingham,
Despite O2 transport, red blood cells fulfill a variety of other functions, all of which also may improve exercise performance. Likely the most important one is the contribution of red blood cells in buffering changes in blood pH by transport of CO2 and by binding of H+ to hemoglobin. Red blood cells also take up metabolites such as lactate that is released from skeletal muscle cells during high intensity exercise. Uptake into red blood cells decreases the plasma concentration of metabolites. Finally, red blood cells seem to be able to decrease peripheral vascular resistance by releasing the vasodilator NO (Stamler et al.,
This review summarizes the mechanisms by which red blood cells warrant O2 supply to the tissues with special emphasis on O2 transport to exercising muscle.
A major mechanism optimizing O2 transport by hemoglobin is the change in Hb-O2 affinity. Changes are very fast and actually occur while red blood cells pass through blood capillaries. Effects of altered Hb-O2 affinity on O2 transport are independent of Hb concentration and total Hb mass in circulation and thus add to the adjustment by changes in erythropoiesis.
The intrinsic O2-affinity of hemoglobin is very high (Weber and Fago,
The physiological significance of an increased Hb-O2 affinity is an improved O2 binding by Hb when the PO2 is low. It is therefore of significance for people exposed to hypoxic environments, where it prevents exaggerated arterial desaturation. A decrease in Hb-O2 affinity improves O2 delivery to cells with a high O2 demand such as in exercising muscle (see below).
A simple approach to estimate the SO2 from PO2 and vice versa has been published by Severinghaus (
Based on a model proposed by Roughton and Severinghaus (
After correction of P50 using this equation to obtain P50,actual, adjusted PO2 (PO2,actual) values can be calculated (Severinghaus,
Then the “Severinhaus-equation” can be used to calculate S from the new PO2 to obtain complete ODCs. A more detailed description of the magnitude of changes in Hb-O2 affinity by allosteric effectors, temperature, and other molecules alone as well as their interactions is reviewed in (Mairbäurl and Weber,
During exercise the increased demand for oxygen is met by increasing muscle blood flow (Laughlin et al.,
Exercising muscle cells release H+, CO2, and lactate into blood capillaries, and there is also a higher temperature in working muscle than in inactive tissues. Blood entering capillaries of exercising muscles is acutely exposed to these changes, which causes a rapid decrease in Hb-O2 affinity. P50 values of ~34–48 mmHg can be estimated from changes in blood gasses (provided e.g., in Sun et al.,
On its way from working muscle to the lung the concentrations of H+ and CO2 in blood are decreased by admixture of blood coming from inactive muscle and other organs. CO2 decreases in alveolar capillaries due to alveolar gas exchange, which further alkalinizes the blood. Thus, the effects of these metabolites on Hb-O2 affinity are attenuated in the lung relative to working muscle. Also the temperature is lower in the lung than in working muscle. Nevertheless, normal values of Hb-O2 affinity are not restored completely during intensive exercise, which is indicated by the slight shift to the right of the ODC in the exercise conditions relative to the resting situation (Figure
When comparing the effects of acid metabolites and the increased body temperature during exercise on Hb-O2 affinity in arterial and muscle capillary blood it is evident that the changes are much greater in working muscle than in the lung. Thus, the greatly increased amount of O2 unloaded from Hb relative to rest easily compensates for arterial desaturation during exercise.
Whereas only 0.03 ml O2 * L−1 * mmHg−1 PO2 at 37°C can be transported in blood in physical solution, one gram of Hb can bind ~1.34 ml of O2. Thus, the presence of a normal amount of Hb per volume of blood increases the amount of O2 that can be transported about 70-fold, which is absolutely essential to meet the normal tissue O2 demand. It is therefore apparent that an increased amount of Hb also increases the amount of O2 that can be delivered to the tissues (Figure
Parameters required to evaluate O2 transport capacity are the Hb concentration in blood (cHb) and hematocrit (Hct), as well as total Hb mass (tHb) and total red blood cell volume (tEV) in circulation. cHb and Hct are easy to measure with standard hematological laboratory equipment. Together with SO2 they indicate the amount of O2 that can be delivered to the periphery per unit volume of cardiac output. tHb and tEV indicate the total amount of O2 that can be transported by blood. A large tHb and tEV allows redirecting O2 to organs with a high O2 demand while maintaining basal O2 supply in less active tissues. Because they are affected by changes in plasma volume (PV) cHb and Hct allow no conclusion on tHb and tEV, respectively.
Results on cHb, Hct and red blood cell count in athletes and their comparison with values obtained in healthy, sedentary individuals are conflicting due to the fact that red blood cell volume and PV change independently and due to the many factors affecting each of these parameters (see below). Establishing normal values for tHb and tEV for athletes is hampered further by the possibility of use of means to increase aerobic capacity such as blood and erythropoietin (EPO) doping.
Many but not all studies show lower Hct in athletes than in sedentary controls (Broun,
Many studies showed that Hct tended to be lower in athletes than in sedentary individuals (Broun,
Changes in Hct occur rapidly. Hct increases during exercise due to a decrease in PV when fluid replacement during exercise is insufficient (Costill et al.,
In a recent review, Thirup (
There appear to be quite large seasonal variations in Hct (relative change up to 15%) with lower values in summer than in winter that might result in season-to-season changes from ~42% in summer and 48% in winter as found among several thousand study participants. Seasonal changes depend on climatic effects with larger differences in countries closer to the equator (Thirup,
The decreased Hct in athletes has been termed “sports anemia.” For a long time it had been explained with increased red blood cell destruction during exercise and thus appeared to be the same phenomenon as the well-known march hemoglobinuria (Broun,
As indicated above, PV is prone to acute changes, whereas changes in total red blood cell mass (or volume) are slow due to slow rates of erythropoiesis (Sawka et al.,
Grehant and Quinquard (
Applying these techniques Kjellberg et al. found that trained individuals had increased tHb (Kjellberg et al.,
Different duration of exercise training (weeks vs. months) appear to explain the diverging results in the studies on tHb and training. Sawka et al. (
Sedentary high altitude residents have an increased tHb in comparison to their low altitude counterparts, where blood volume has been found to be increased from ~80 to ~100 ml/kg (Hurtado,
Based on the raise in tEV upon ascent to high altitude and by training in normoxia it was concluded that effects of training and high altitude exposure on tHb might be additive, and that training at simulated altitude or by ascent to moderate or high altitude should cause an even further increase than training in normoxia. However, results are inconsistent ranging from no effect (Svedenhag et al.,
It has been recognized by Bert (
One such oxygen dependent mechanism is the control of expression by hypoxia inducible factors, HIF (Semenza,
In his review Haase (
In the adult, the oxygen sensor controlling EPO production is in the kidney, where the cells producing EPO have been shown to be peritubular fibroblasts in the renal cortex (Maxwell et al.,
EPO released into blood has many functions other than stimulating erythropoiesis (for review see Sasaki,
The increased tHb and tEV in trained athletes indicates that exercise stimulates erythropoiesis. An additional marker is the elevation of reticulocytes counts which can be observed within 1–2 days (Schmidt et al.,
Whereas the control of erythropoiesis in hypoxic and anemic hypoxia is well-understood, the signals stimulating erythropoiesis upon training in normoxia are unclear. Exposure to hypoxia causes a fast increase in EPO (Eckardt et al.,
Arguments for hypoxia as the relevant trigger for exercise induced erythropoiesis are sparse, and are at best indirect. Even during heavy exercise there is only a small decrease in arterial PO2 (see chapter 2, arterial O2 loading) that by itself will barely be sufficient to cause relevant renal EPO production. There is, however, a considerable decrease in renal blood flow with increasing exercise intensity that decreases renal O2 supply (for an excellent review on splanchnic blood flow regulation in exercise see Laughlin et al.,
A variety of humoral factors known to affect erythropoiesis also change during exercise. Androgens are long known for their stimulatory effect on erythropoiesis by stimulation of EPO release, increasing bone marrow activity, and iron incorporation into the red cells, which is best indicated by polycythemia as a consequence of androgen therapy (Shahidi,
Stress hormones such as catecholamines and cortisol stimulate the release of reticulocytes from the bone marrow and possibly also enhance erythropoiesis (Dar et al.,
Hematocrit not only affects the amount of O2 that can be carried per volume of blood but also affects the rheological properties of blood. Due to its composition of plasma and blood cells it behaves as a non-Newtonian fluid, whose inner viscosity is affected by the shear forces and is determined by the concentration of plasma proteins (plasma viscosity), the physico-chemical properties of the red blood cell plasma membrane (deformability) and cellular hemoglobin concentration (cytosolic viscosity), the flow velocity (aggregation), and temperature (for review see El-Sayed et al.,
Because of the axial migration of blood cells when blood is moved with a high velocity it has been argued that plasma viscosity is the major determinant of whole blood viscosity (Rand et al.,
Exercise and training affect all of the above mentioned determinants of whole blood viscosity. There is a well-documented increase in whole blood viscosity during exercise which reverses rapidly (for review see El-Sayed et al.,
Together these results indicate that the increase in whole blood viscosity during exercise is caused by the combined effects of increased plasma viscosity and decreased deformability of the red blood cells, and potentially impairs microcirculation and thus O2 delivery to working muscle. Moderation of this effect might be brought about by NO released from endothelium and red blood cells with increased shear stress, because nitrosylation of cytoskeletal proteins in the red blood cell membrane seems to improve deformability (Grau et al.,
Precise control of regional blood flow is required to match substrate demand and removal of metabolites, which is of particular importance when the metabolic activity is high such as in exercising skeletal muscle. Nitric oxide (NO) is an important signaling molecule that causes local vasodilation. It is typically formed in vascular endothelial cells upon a variety of stimuli, the most important during exercise likely being shear stress (Pohl et al.,
It has been shown experimentally that NO released from red blood cells causes vasodilation when the shear stress is increased and when the tissue is made hypoxic (Ulker et al.,
ATP in plasma is another stimulus for endothelial NO production (Sprague et al.,
The major stimulus for ATP release from red blood cells seems to be mechanical deformation (Sprague et al.,
Taken together these results indicate that red blood cells support local vasodilation in tissues with a high O2 demand by directly mediating NO release and enzymatic production and by release of ATP, which causes NO release from endothelial cells by mechanisms, which are greatly enhanced in exercise when shear stress is increased by increased blood flow, O2 is low due to increased consumption, and the increase in temperature.
There are many mechanisms that contribute to an increased tissue oxygen supply during exercise. Figure
The author declares that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.