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Regulation of Red Blood Cell Volume with Exercise Training

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ABSTRACT

Hypervolemia is a hallmark of endurance training (ET) and manifests by similar elevations in plasma (PV) and red blood cell volume (RBCV) so that hematocrit largely remains unaltered following weeks/months of training. While the mechanisms facilitating PV expansion with ET have been previously reviewed extensively this is not the case for RBCV. Endurance champions may have 40% more RBCV than controls and RBCV may increase up to 10% following months of regular exercise training in healthy individuals. Such adaptations are the main factor leading to concomitant changes in maximal oxygen uptake. The increase in RBCV is preceded by that of PV after few ET sessions, which in turn transiently decreases the hematocrit. The “critmeter” theory suggests that O2 sensors located within the juxtamedullary apparatus regulate the hematocrit via modulation of renal erythropoietin (EPO) production according to arterial O2 content‐dependent changes in tissue O2 pressure. Hence, the initial decrease in hematocrit can be considered as a primary mechanism facilitating RBCV expansion with ET. Furthermore, after a single endurance exercise bout blood volume‐regulating hormones ANGII and VPN increase transiently. Both stimulate renal EPO production. Catecholamines and cortisol, stress hormones acutely increased by endurance exercise, may facilitate the release of red blood cells from the bone marrow, thus possibly contributing to ET‐induced erythropoiesis. These and other endocrine effects could be enhanced by the hyperplasia of the hematopoietic bone marrow observed in endurance athletes. © 2019 American Physiological Society. Compr Physiol 9:149‐164, 2019.

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Figure 1. Figure 1. Relationship of hemoglobin mass and blood volumes with aerobic capacity. Aerobic capacity, represented by maximal oxygen consumption (VO2max), is closely associated with blood volumes in humans along the continuum of VO2max from healthy young untrained individuals to Olympic champions in endurance disciplines. The strongest determinants of VO2max are red blood cell volume (RBCV) and hemoglobin mass (nHb), followed by blood volume (BV) and plasma volume (PV). The concentration of hemoglobin in blood ([Hb]) is not associated with VO2max, underlining the importance of volumetric variables facilitating cardiac output over relatively uniform [Hb] values.
Figure 2. Figure 2. Changes in blood volumes with endurance training. This figure presents absolute (A) and relative (B) changes in blood volume (BV) (circles), red blood cell volume (RBCV) (squares), and plasma volume (PV) (triangles) throughout 8 weeks of a typical endurance training program (3‐4 × 60 min, moderate‐to‐high intensity cycle ergometry sessions per week) in healthy young untrained individuals. Endurance training elicits substantial increases in RBCV from week 4, preceded by marked PV expansion during the initial weeks, resulting in reduced hematocrit. At week 8, RBCV is further increased while PV expansion is slightly attenuated, thus approaching normal hematocrit levels.
Figure 3. Figure 3. Acute effect of endurance exercise on circulating erythropoietin (EPO). This figure shows plasma EPO concentration from 7 to 10 AM in healthy young untrained individuals following a session of endurance exercise (1‐h of cycle ergometry at 55% of maximal power output) (filled circles) or 1‐h rest (open circles). Plasma EPO concentration acutely increases following endurance exercise. This increase is accentuated 3 h after stopping exercise, independently of exercise‐induced hemoconcentration.
Figure 4. Figure 4. Mechanisms underlying the effect of endurance exercise on circulating erythropoietin (EPO): the critmeter hypothesis. Endurance exercise‐induced plasma volume expansion lowers hematocrit and arterial O2 content, resulting in decreased tissue O2 pressure in the juxtamedullary region of the cortical labyrinth in the kidney, stimulating EPO‐producing cells (peritubular fibroblast‐like cells). Augmented circulating EPO enhance erythropoiesis in the bone marrow, increasing red blood cell volume and hence tending to restore hematocrit and arterial O2 content, closing a negative feedback loop.
Figure 5. Figure 5. Mechanisms underlying the effect of endurance exercise on circulating erythropoietin (EPO): baroreflex‐endocrine responses to reduced central venous pressure. Central venous pressure, which reflects the filling state of the cardiovascular system, is reduced for several hours after endurance exercise, in part due to peripheral vasodilation. The reduction in central venous pressure is sensed by cardiopulmonary and arterial baroreceptors, triggering the release of blood volume (BV)‐regulating hormones such as angiotensin II (ANGII) and vasopressin (VPN). These hormones stimulate renal EPO production via direct activation of renal receptors as well as through the increase of sodium reabsorption leading to decreased tissue O2 pressure in peritubular fibroblast‐like cells. Ultimately, the EPO‐induced enhancement of red blood cell volume contributes, along with plasma volume expansion, to blood pressure homeostasis with endurance training.
Figure 6. Figure 6. Acute effect of endurance exercise on endocrine factors modulating bone marrow erythropoiesis. Besides erythropoietin, several hormones possessing erythropoietic activity are transiently elevated with endurance exercise. Catecholamines augment the release of hematopoietic stem cells from the bone marrow, mediated by chemokine stromal cell derived factor‐1 (SDF‐1). Another stress hormone, cortisol, stimulates differentiation, and mobilization of erythroid progenitor cells (EPCs) via Notch signaling pathways. Furthermore, growth hormone (GH) and its mediator insulin‐like growth factor 1 (IGF‐1) can induce erythroid cell growth and differentiation in the bone marrow. Overall, endurance exercise enhances plasma erythropoietic activity via redundant endocrine pathways.


Figure 1. Relationship of hemoglobin mass and blood volumes with aerobic capacity. Aerobic capacity, represented by maximal oxygen consumption (VO2max), is closely associated with blood volumes in humans along the continuum of VO2max from healthy young untrained individuals to Olympic champions in endurance disciplines. The strongest determinants of VO2max are red blood cell volume (RBCV) and hemoglobin mass (nHb), followed by blood volume (BV) and plasma volume (PV). The concentration of hemoglobin in blood ([Hb]) is not associated with VO2max, underlining the importance of volumetric variables facilitating cardiac output over relatively uniform [Hb] values.


Figure 2. Changes in blood volumes with endurance training. This figure presents absolute (A) and relative (B) changes in blood volume (BV) (circles), red blood cell volume (RBCV) (squares), and plasma volume (PV) (triangles) throughout 8 weeks of a typical endurance training program (3‐4 × 60 min, moderate‐to‐high intensity cycle ergometry sessions per week) in healthy young untrained individuals. Endurance training elicits substantial increases in RBCV from week 4, preceded by marked PV expansion during the initial weeks, resulting in reduced hematocrit. At week 8, RBCV is further increased while PV expansion is slightly attenuated, thus approaching normal hematocrit levels.


Figure 3. Acute effect of endurance exercise on circulating erythropoietin (EPO). This figure shows plasma EPO concentration from 7 to 10 AM in healthy young untrained individuals following a session of endurance exercise (1‐h of cycle ergometry at 55% of maximal power output) (filled circles) or 1‐h rest (open circles). Plasma EPO concentration acutely increases following endurance exercise. This increase is accentuated 3 h after stopping exercise, independently of exercise‐induced hemoconcentration.


Figure 4. Mechanisms underlying the effect of endurance exercise on circulating erythropoietin (EPO): the critmeter hypothesis. Endurance exercise‐induced plasma volume expansion lowers hematocrit and arterial O2 content, resulting in decreased tissue O2 pressure in the juxtamedullary region of the cortical labyrinth in the kidney, stimulating EPO‐producing cells (peritubular fibroblast‐like cells). Augmented circulating EPO enhance erythropoiesis in the bone marrow, increasing red blood cell volume and hence tending to restore hematocrit and arterial O2 content, closing a negative feedback loop.


Figure 5. Mechanisms underlying the effect of endurance exercise on circulating erythropoietin (EPO): baroreflex‐endocrine responses to reduced central venous pressure. Central venous pressure, which reflects the filling state of the cardiovascular system, is reduced for several hours after endurance exercise, in part due to peripheral vasodilation. The reduction in central venous pressure is sensed by cardiopulmonary and arterial baroreceptors, triggering the release of blood volume (BV)‐regulating hormones such as angiotensin II (ANGII) and vasopressin (VPN). These hormones stimulate renal EPO production via direct activation of renal receptors as well as through the increase of sodium reabsorption leading to decreased tissue O2 pressure in peritubular fibroblast‐like cells. Ultimately, the EPO‐induced enhancement of red blood cell volume contributes, along with plasma volume expansion, to blood pressure homeostasis with endurance training.


Figure 6. Acute effect of endurance exercise on endocrine factors modulating bone marrow erythropoiesis. Besides erythropoietin, several hormones possessing erythropoietic activity are transiently elevated with endurance exercise. Catecholamines augment the release of hematopoietic stem cells from the bone marrow, mediated by chemokine stromal cell derived factor‐1 (SDF‐1). Another stress hormone, cortisol, stimulates differentiation, and mobilization of erythroid progenitor cells (EPCs) via Notch signaling pathways. Furthermore, growth hormone (GH) and its mediator insulin‐like growth factor 1 (IGF‐1) can induce erythroid cell growth and differentiation in the bone marrow. Overall, endurance exercise enhances plasma erythropoietic activity via redundant endocrine pathways.
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Teaching Material

D. Montero, C. Lundby. Regulation of Red Blood Cell Volume with Exercise Training. Compr Physiol 9: 2019, 149-164.

Didactic Synopsis

Major Teaching Points:

  • Hemoglobin mass and/or red blood cell volume (RBCV) are major determinants of maximal oxygen uptake (VO2max).
  • Endurance athletes may have up to 40% greater RBCV than healthy untrained individuals.
  • Endurance training facilitates RBCV expansion and thereby also VO2max improvement.
  • Prior to RBCV expansion endurance training leads to an about 10% increase in plasma volume (PV), which decreases hematocrit transiently.
  • The initial drop in hematocrit is proposed being sensed by kidney O2 sensors located in the juxtamedullary apparatus, which stimulate the release of erythropoietin (EPO).
  • Transient post-endurance exercise rises in blood volume-regulating hormones contributing to PV expansion (angiotensin II, vasopressin) directly induce renal EPO production.
  • Circulating hormones enhanced during and after endurance exercise such as catecholamines, cortisol and growth hormone may facilitate proliferation, differentiation, and/or release of red blood cells from the hematopoietic bone marrow.

Didactic Legends

The figures—in a freely downloadable PowerPoint format—can be found on the Images tab along with the formal legends published in the article. The following legends to the same figures are written to be useful for teaching.

Figure 1 Relationship of hemoglobin mass and blood volumes with aerobic capacity. Teaching points: Aerobic capacity, represented by maximal oxygen consumption (VO2max), is closely associated with blood volumes in humans along the continuum of VO2max from healthy young untrained individuals to Olympic champions in endurance disciplines. The strongest determinants of VO2max are red blood cell volume (RBCV) and hemoglobin mass (nHb), followed by blood volume (BV) and plasma volume (PV). The concentration of hemoglobin in blood ([Hb]) is not associated with VO2max, underlining the importance of volumetric variables facilitating cardiac output over relatively uniform [Hb] values.

Figure 2 Changes in blood volumes with endurance training. Teaching points: This figure presents absolute (A) and relative (B) changes in blood volume (BV) (circles), red blood cell volume (RBCV) (squares), and plasma volume (PV) (triangles) throughout 8 weeks of a typical endurance training program (3-4 × 60 min, moderate-to-high intensity cycle ergometry sessions per week) in healthy young untrained individuals. Endurance training elicits substantial increases in RBCV from week 4, preceded by marked PV expansion during the initial weeks, resulting in reduced hematocrit. At week 8, RBCV is further increased while PV expansion is slightly attenuated, thus approaching normal hematocrit levels.

Figure 3 Acute effect of endurance exercise on circulating erythropoietin (EPO). Teaching points: This figure shows plasma EPO concentration from 7 to 10 AM in healthy young untrained individuals following a session of endurance exercise (1-h of cycle ergometry at 55% of maximal power output) (filled circles) or 1-h rest (open circles). Plasma EPO concentration acutely increases following endurance exercise. This increase is accentuated 3 hours after stopping exercise, independently of exercise-induced hemoconcentration.

Figure 4 Mechanisms underlying the effect of endurance exercise on circulating erythropoietin (EPO): the critmeter hypothesis. Teaching points: Endurance exercise-induced plasma volume expansion lowers hematocrit and arterial O2 content, resulting in decreased tissue O2 pressure in the juxtamedullary region of the cortical labyrinth in the kidney, stimulating EPO-producing cells (peritubular fibroblast-like cells). Augmented circulating EPO enhance erythropoiesis in the bone marrow, increasing red blood cell volume and hence tending to restore hematocrit and arterial O2 content, closing a negative feedback loop.

Figure 5 Mechanisms underlying the effect of endurance exercise on circulating erythropoietin (EPO): baroreflex-endocrine responses to reduced central venous pressure. Teaching points: Central venous pressure, which reflects the filling state of the cardiovascular system, is reduced for several hours after endurance exercise, in part due to peripheral vasodilation. The reduction in central venous pressure is sensed by cardiopulmonary and arterial baroreceptors, triggering the release of blood volume (BV)-regulating hormones such as angiotensin II (ANGII) and vasopressin (VPN). These hormones stimulate renal EPO production via direct activation of renal receptors as well as through the increase of sodium reabsorption leading to decreased tissue O2 pressure in peritubular fibroblast-like cells. Ultimately, the EPO-induced enhancement of red blood cell volume contributes, along with plasma volume expansion, to blood pressure homeostasis with endurance training.

Figure 6 Acute effect of endurance exercise on endocrine factors modulating bone marrow erythropoiesis. Teaching points: Besides erythropoietin, several hormones possessing erythropoietic activity are transiently elevated with endurance exercise. Catecholamines augment the release of hematopoietic stem cells from the bone marrow, mediated by chemokine stromal cell derived factor-1 (SDF-1). Another stress hormone, cortisol, stimulates differentiation and mobilization of erythroid progenitor cells (EPCs) via Notch signaling pathways. Furthermore, growth hormone (GH) and its mediator insulin-like growth factor 1 (IGF-1) can induce erythroid cell growth and differentiation in the bone marrow. Overall, endurance exercise enhances plasma erythropoietic activity via redundant endocrine pathways.

 


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How to Cite

David Montero, Carsten Lundby. Regulation of Red Blood Cell Volume with Exercise Training. Compr Physiol 2018, 9: 149-164. doi: 10.1002/cphy.c180004