Kidney-synthesized erythropoietin is the main source for the hypoxia-induced increase in plasma erythropoietin in adult humans

Purpose: Erythropoietin (EPO) is mainly synthesized within renal peritubular fibroblasts, and also other tissues such as the liver possess the ability. However, to what extent non-kidney produced EPO contributes to the hypoxia-induced increase in circulating EPO in adult humans remains unclear. Methods: We aimed to quantify this by assessing the distribution of EPO glycoforms which are characterized by posttranslational glycosylation patterns specific to the synthesizing cell. The analysis was performed on samples obtained in seven healthy volunteers before, during and after 1month of sojourn at 3,454m altitude. Results: Umbilical cord (UC) plasma served as control. As expected a peak (p<0.05) in urine (2.3±0.5-fold) and plasma (3.3±0.5-fold) EPO was observed on day 1 of high-altitude exposure, and thereafter the concentration decreased for the urine sample obtained after 26days at altitude, but remained elevated (p<0.05) by 1.5±0.2-fold above the initial sea level value for the plasma sample. The EPO glycoform heterogeneity, in the urine samples collected at altitude, did not differ from values at sea level, but were markedly lower (p<0.05) than the mean percent migrated isoform (PMI) for the umbilical cord samples. Conclusion: Our studies demonstrate (1) UC samples express a different glycoform distribution as compared to adult humans and hence illustrates the ability to synthesis EPO in non-kidney cells during fetal development (2) as expected hypoxia augments circulating EPO in adults and the predominant source here for remains being kidney derived

Prolonged heat acclimation and aerobic performance in endurance trained athletes

Frontiers is fully compliant with open access mandates, by publishing its articles under the Creative Commons Attribution licence (CC-BY). Funder mandates such as those by the Wellcome Trust (UK), National Institutes of Health (USA) and the Australian Research Council (Australia) are fully compatible with publishing in Frontiers. Authors retain copyright of their work and can deposit their publication in any repository. The work can be freely shared and adapted provided that appropriate credit is given and any changes specified.Heat acclimation (HA) involves physiological adaptations that directly promote exercise performance in hot environments. However, for endurance-athletes it is unclear if adaptations also improve aerobic capacity and performance in cool conditions, partly because previous randomized controlled trial (RCT) studies have been restricted to short intervention periods. Prolonged HA was therefore deployed in the present RCT study including 21 cyclists [38 ± 2 years, 184 ± 1 cm, 80.4 ± 1.7 kg, and maximal oxygen uptake (VO2max) of 58.1 ± 1.2 mL/min/kg; mean ± SE] allocated to either 5½ weeks of training in the heat [HEAT (n = 12)] or cool control [CON (n = 9)]. Training registration, familiarization to test procedures, determination of VO2max, blood volume and 15 km time trial (TT) performance were assessed in cool conditions (14°C) during a 2-week lead-in period, as well as immediately pre and post the intervention. Participants were instructed to maintain total training volume and complete habitual high intensity intervals in normal settings; but HEAT substituted part of cool training with 28 ± 2 sessions in the heat (1 h at 60% VO2max in 40°C; eliciting core temperatures above 39°C in all sessions), while CON completed all training in cool conditions. Acclimation for HEAT was verified by lower sweat sodium [Na+], reduced steady-state heart rate and improved submaximal exercise endurance in the heat. However, when tested in cool conditions both peak power output and VO2max remained unchanged for HEAT (pre 60.0 ± 1.5 vs. 59.8 ± 1.3 mL O2/min/kg). TT performance tested in 14°C was improved for HEAT and average power output increased from 298 ± 6 to 315 ± 6 W (P < 0.05), but a similar improvement was observed for CON (from 294 ± 11 to 311 ± 10 W). Based on the present findings, we conclude that training in the heat was not superior compared to normal (control) training for improving aerobic power or TT performance in cool conditions.publishedVersio

Kidney-synthesized erythropoietin is the main source for the hypoxia-induced increase in plasma erythropoietin in adult humans

PURPOSE Erythropoietin (EPO) is mainly synthesized within renal peritubular fibroblasts, and also other tissues such as the liver possess the ability. However, to what extent non-kidney produced EPO contributes to the hypoxia-induced increase in circulating EPO in adult humans remains unclear. METHODS We aimed to quantify this by assessing the distribution of EPO glycoforms which are characterized by posttranslational glycosylation patterns specific to the synthesizing cell. The analysis was performed on samples obtained in seven healthy volunteers before, during and after 1 month of sojourn at 3,454 m altitude. RESULTS Umbilical cord (UC) plasma served as control. As expected a peak (p < 0.05) in urine (2.3 ± 0.5-fold) and plasma (3.3 ± 0.5-fold) EPO was observed on day 1 of high-altitude exposure, and thereafter the concentration decreased for the urine sample obtained after 26 days at altitude, but remained elevated (p < 0.05) by 1.5 ± 0.2-fold above the initial sea level value for the plasma sample. The EPO glycoform heterogeneity, in the urine samples collected at altitude, did not differ from values at sea level, but were markedly lower (p < 0.05) than the mean percent migrated isoform (PMI) for the umbilical cord samples. CONCLUSION Our studies demonstrate (1) UC samples express a different glycoform distribution as compared to adult humans and hence illustrates the ability to synthesis EPO in non-kidney cells during fetal development (2) as expected hypoxia augments circulating EPO in adults and the predominant source here for remains being kidney derived

Hematological adaptations to prolonged heat acclimation in endurance-trained males

Frontiers is fully compliant with open access mandates, by publishing its articles under the Creative Commons Attribution licence (CC-BY). Authors retain copyright of their work and can deposit their publication in any repository. The work can be freely shared and adapted provided that appropriate credit is given and any changes specified.Heat acclimation is associated with plasma volume (PV) expansion that occurs within the first week of exposure. However, prolonged effects on hemoglobin mass (Hbmass) are unclear as intervention periods in previous studies have not allowed sufficient time for erythropoiesis to manifest. Therefore, Hbmass, intravascular volumes, and blood volume (BV)-regulating hormones were assessed with 5½ weeks of exercise-heat acclimation (HEAT) or matched training in cold conditions (CON) in 21 male cyclists [(mean ± SD) age: 38 ± 9 years, body weight: 80.4 ± 7.9 kg, VO2peak: 59.1 ± 5.2 ml/min/kg]. HEAT (n = 12) consisted of 1 h cycling at 60% VO2peak in 40°C for 5 days/week in addition to regular training, whereas CON (n = 9) trained exclusively in cold conditions (<15°C). Before and after the intervention, Hbmass and intravascular volumes were assessed by carbon monoxide rebreathing, while reticulocyte count and BV-regulating hormones were measured before, after 2 weeks and post intervention. Total training volume during the intervention was similar (p = 0.282) between HEAT (509 ± 173 min/week) and CON (576 ± 143 min/week). PV increased (p = 0.004) in both groups, by 303 ± 345 ml in HEAT and 188 ± 286 ml in CON. There was also a main effect of time (p = 0.038) for Hbmass with +34 ± 36 g in HEAT and +2 ± 33 g in CON and a tendency toward a higher increase in Hbmass in HEAT compared to CON (time × group interaction: p = 0.061). The Hbmass changes were weakly correlated to alterations in PV (r = 0.493, p = 0.023). Reticulocyte count and BV-regulating hormones remained unchanged for both groups. In conclusion, Hbmass was slightly increased following prolonged training in the heat and although the mechanistic link remains to be revealed, the increase could represent a compensatory response in erythropoiesis secondary to PV expansion.publishedVersio

The impact of hypoxia on aerobic exercise capacity

Acute hypoxia impairs aerobic exercise by reducing the capacity for maximal O2 uptake (VO2max). This is mainly the consequence of a lower arterial O2 content (caO2) and, in severe hypoxia, cardiac output during maximal exercise as the combination of these two factors attenuates convective O2 supply to the exercising muscle cells. Nevertheless, the incapacitating effect of hypoxia is partially restored during prolonged exposure as an increased renal erythropoietin release induces polycythemia that normalizes caO2. Since this mechanism may benefit performance not only in hypoxia but also in normoxia different forms of altitude training were developed all aiming to enhance athletic performance at sea level. The purpose of the present project was to enhance our understanding regarding the interaction between both, acute and chronic hypoxia and aerobic exercise. In acute hypoxia the contribution of the intrinsic responses of the pulmonary and the cerebral circulation to the reduction in VO2max was investigated. Specifically, we hypothesized that the hypoxiainduced rise in pulmonary artery pressure induces exercise limitations by increasing right ventricular afterload and/ or promoting pulmonary ventilation-perfusion mismatch. Furthermore, we suggested that the cerebral hypoxia that develops during exercise at altitude would limit VO2max by accelerating the development of supraspinal fatigue. Regarding chronic hypoxia we tested the efficacy and underlying mechanisms of the contemporary altitude training strategy, i.e. the Live High – Train Low approach, on elite endurance athletes in a double-blinded and placebo-controlled study design. The results collected in three independent studies revealed the following: 1) At 4,559 m altitude pulmonary vasodilation induced by the glucocorticoid Dexamethasone elevates VO2max of individuals present with an excessive vasoconstrictive response to hypoxia without affecting arterial O2 saturation (SaO2). A direct comparison to normal individuals further suggested a larger hypoxia-induced exercise impairment in these individuals but also no differences in SaO2 during maximal exercise. We thus conclude that hypoxic pulmonary vasoconstriction may contribute to the reduced VO2max in acute hypoxia potentially by increasing right ventricular afterload and thereby attenuating cardiac output. 2) Although administration of CO2 during exercise at 3,454 m altitude elevated cerebral blood flow and, as a consequence, cerebral oxygenation, VO2max remained unaffected. This indicates that the contribution of the reduced cerebral oxygenation on the limitation of VO2max in hypoxia is neglectable. Nevertheless, as a VO2max test induces progressive demand for muscular O2 supply, the capacity of the O2 transport system might have been exhausted before supraspinal fatigue occurred, and thus we cannot exclude that the decline in cerebral oxygenation may play a role during submaximal exercise in hypoxia. 3) Four weeks of discontinuous (16 hours per day) exposure to normobaric hypoxia corresponding to 3,000 m combined with daily training in normoxia failed to benefit the performance of elite endurance athletes. This was explained by the absence of an effect of hypoxia on total red cell volume. These findings suggest a potential role of a placeboeffect in earlier studies and indicate that four weeks of discontinuous hypoxic exposure may be insufficient to induce physiological adaptations. Athletes should take this into consideration before shouldering the inconveniences associated with Live High – Train Low altitude training. In brief, the present results support a limiting role of pulmonary vasoconstriction but not of attenuated cerebral oxygenation on VO2max in hypoxia. They further indicate that altitude training following the Live High – Train Low strategy may not be superior to conventional endurance training

Cerebrovascular reactivity is increased with acclimatization to 3,454 m altitude

Controversy exists regarding the effect of high-altitude exposure on cerebrovascular CO2 reactivity (CVR). Confounding factors in previous studies include the use of different experimental approaches, ascent profiles, duration and severity of exposure and plausibly environmental factors associated with altitude exposure. One aim of the present study was to determine CVR throughout acclimatization to high altitude when controlling for these. Middle cerebral artery mean velocity (MCAv mean) CVR was assessed during hyperventilation (hypocapnia) and CO2 administration (hypercapnia) with background normoxia (sea level (SL)) and hypoxia (3,454 m) in nine healthy volunteers (26 ± 4 years (mean ± s.d.)) at SL, and after 30 minutes (HA0), 3 (HA3) and 22 (HA22) days of high-altitude (3,454 m) exposure. At altitude, ventilation was increased whereas MCAv mean was not altered. Hypercapnic CVR was decreased at HA0 (1.16% ± 0.16%/mm Hg, mean ± s.e.m.), whereas both hyper- and hypocapnic CVR were increased at HA3 (3.13% ± 0.18% and 2.96% ± 0.10%/mm Hg) and HA22 (3.32% ± 0.12% and 3.24% ± 0.14%/mm Hg) compared with SL (1.98% ± 0.22% and 2.38% ± 0.10%/mm Hg; P < 0.01) regardless of background oxygenation. Cerebrovascular conductance (MCAv mean/mean arterial pressure) CVR was determined to account for blood pressure changes and revealed an attenuated response. Collectively our results show that hypocapnic and hypercapnic CVR are both elevated with acclimatization to high altitude