Exercise Performance In Hypoxia Research Articles

Impact of Respiratory Muscle Training on Exercise Tolerance in Hypobaric Hypoxia

Hypoxia and certain chronic diseases can intensify the work of breathing, potentially impacting the muscle hyperemic response during exercise and overall exercise performance. Respiratory muscle training (RMT) has been observed to decrease perceived effort under hypoxic conditions; however, it remains unclear if RMT boosts exercise performance in acute hypoxia. We investigated whether 4 weeks of RMT could enhance maximal and submaximal exercise performance in hypoxia (PB=425 mmHg, ~4876 m). Seven adult males underwent a 250 kJ submaximal (RPE 15-17) cycling trial in hypoxia, followed by an incremental test to maximal exertion. After 4 weeks of RMT under normoxic conditions, these tests were repeated in hypoxia. Although six of the participants displayed improvements in submaximal exercise performance, these numerical differences failed to reach statistical significance. However, RMT did raise VO2max peak power (Pre-RMT: 242.62 ± 35, Post-RMT: 251.85 ± 38 W, p=0.04). Moreover, even with an increased HR during the submaximal exercise trial after RMT (Pre-RMT:154.14 ± 16, Post-RMT: 160.86 ± 12, p<0.05), the RPE showed no significant difference during the test (Pre-RMT: 17.43 ± 0.79, Post-RMT: 17.43 ± 0.53, P>0.05). Despite this, no substantial increase in hypoxic submaximal exercise performance was observed, likely due to the small sample size. These findings suggest RMT might increase hypoxic exercise tolerance by reducing perceived exertion for a given HR. This work was supported by funding from the United States Special Operations Command (USSOCOM) and the National Institutes of Health (2L30HL134123-03). This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Inspiratory Muscle Training: Improvement of Exercise Performance With Acute Hypoxic Exposure.

To determine whether chronic IMT improves submaximal-exercise performance with acute hypoxic exposure. A total of 14 endurance-trained men completed a 20-km cycling time trial (TT) in normobaric hypoxia (fraction of inspired oxygen [FiO2] = 0.16) before and after either 6 wk of an IMT protocol consisting of inspiratory loads equivalent to 80% of sustained maximal inspiratory pressure (n = 9) or a SHAM protocol (30% of sustained maximal inspiratory pressure; n = 5). In the IMT group, 20-km TT performance significantly improved by 1.45 (2.0%), P = .03, after the 6-wk intervention. The significantly faster TT times were accompanied by a higher average V˙E (pre vs post: 99.3 [14.5] vs 109.9 [18.0]L·min-1, P = .01) and absolute oxygen uptake (pre vs post: 3.39 [0.52] vs 3.60 [0.58]L·min-1, P = .010), with no change in ratings of perceived exertion or dyspnea (P > .06). There were no changes in TT performance in the SHAM group (P = .45). These data suggest that performing 6 wk of IMT may benefit hypoxic endurance exercise performance lasting 30-40min.

5-Hydroxymethylfurfural and α-ketoglutaric acid supplementation increases oxygen saturation during prolonged exercise in normobaric hypoxia

This double-blinded, randomized and placebo-controlled, crossover study investigated whether α-ketoglutaric-acid (α-KG) and 5-hydroxymethylfurfural (5-HMF) supplementation improves exercise performance in hypoxia and affects physiological responses during the exercise task. Eight moderately trained male participants (age: 25.3±2.0 y, VO2max: 48.0±8.3ml/min/kg) performed an incremental exercise test to exhaustion in normoxia and two 2-hour cycle time trial (TT) tests in hypoxia (3,500m) each separated by 1-week. Prior to the TT, participants supplemented with either α-KG and 5-HMF or placebo (random order). Supplementation did not improve TT performance at altitude and did not affect heart rate, effort perception and oxidative stress levels (p>0.05). Oxygen saturation (SpO2) was enhanced during the α-KG and 5-HMF supplementation trial (79.5±3.3 vs. 78.2±3.7%, p=0.026). Even though TT performance was unaffected, the enhanced SpO2 - possibly originated from changed O2-affinity - deserves further consideration as the exercise performance decline at altitude is strongly linked to the SpO2 decline. The inclusion of moderately fit participants, not specifically cycle trained, might have prevented any visible performance enhancement.

Hypoxic Exercise Performance with an Antihistamine: Influence of Aerobic Fitness

At altitude, impairments in pulmonary oxygen diffusion and oxygen delivery have a detrimental effect on endurance exercise tolerance. Analogues of over-the-counter antihistamines have been shown to improve oxyhemoglobin saturation (SpO2) and oxygen delivery during heavy exercise, but hypoxic performance outcomes have not been studied. PURPOSE: To determine the effect of the antihistamine, cetirizine (Zyrtec®) on hypoxic exercise performance in recreationally active subjects. METHODS: Eight subjects [6 men, 2 women; age = 22 ± 1y; V̇O2max = 44.3 ± 8.3 ml·kg-1·min-1 (range: 32.0-55.2 ml·kg-1·min-1) ] completed constant load exercise at 45% and 65% of normoxic VO2max and an 8km time trial in conditions of normoxia (NORM), hypoxia with placebo (HYP+P), and hypoxia with cetirizine (HYP+C). Subjects inspired 15% oxygen to simulate an altitude of 2,500m for HYP+P and HYP+C and were given a 10mg fixed-dose of cetirizine one hour prior to exercise for HYP+C. Measures of SpO2 via pulse oximetry and muscle tissue oxyhemoglobin concentration ([OxyHb+Mb]) of the vastus lateralis via near infrared spectroscopy were continuously measured throughout exercise. RESULTS: There was no significant difference (P ≥ 0.232) in SpO2 between HYP+P and HYP+C during the 45% (89 ± 6% vs. 89 ± 4%) and 65% (87± 6% vs. 85 ± 5%) constant loads. The cetirizine intervention had a significant effect (P = 0.005) on Δ [OxyHb+Mb] (%) during the 65% constant load with a difference between HYP+P and HYP+C (-28 ± 45% vs. +14 ± 16%). There was no difference in 8km performance times between HYP+P and HYP+C (18.08 ± 2.87 min vs. 17.03 ± 1.92 min, P = 0.112, dz= 0.63). However, when co-varied by V̇O2max, cetirizine had a significant effect (P = 0.047) on 8km time trial performance with a difference of 1.06 min (95% CI [0.01, 2.11]) between HYP+P and HYP+C. VO2max accounted for 53% of the variance in time trial performance changes between interventions. CONCLUSION: Cetirizine improves endurance exercise performance in hypoxia with a larger effect on individuals with lower V̇O2max. The cetirizine intervention resulted in greater skeletal muscle oxygenation at 65% V̇O2max with hypoxia. These results would suggest that cetirizine does not improve SpO2, but improves hypoxic exercise performance perhaps through enhanced oxygen delivery to the skeletal muscles.

Dark Chocolate and Exercise Performance in Hypoxia

Dark Chocolate and Exercise Performance in Hypoxia

Sildenafil does not improve performance in 16.1 km cycle exercise time-trial in acute hypoxia.

Sildenafil is a pulmonary vasodilator that has potential to mitigate the decrement in endurance performance caused by hypoxic pulmonary vasoconstriction. The purpose of this study was to determine the effects of sildenafil on pulmonary artery pressure, cardiac output, pulse oxygen saturation, and exercise performance at moderate simulated altitude. We hypothesized that sildenafil would reduce the decline in exercise performance in hypoxia by blunting the rise in pulmonary artery pressure and causing a relative increase in cardiac output and oxygen saturation. Twelve endurance trained men performed three experimental cycling trials at sea level and simulated moderate altitude of 3,000m (FIO2 = 0.147) after ingesting either a placebo or sildenafil 50 mg capsule in a double blinded fashion. Each test consisted of a warmup period, a 15-minute steady state period at 60% of peak power output, and a 16.1 km time-trial. All subjects experienced a decline in maximal exercise capacity in hypoxia that ranged from 6% to 24%. This decline was correlated with the reduction in pulse oxygen saturation in hypoxic maximal exercise. Sildenafil had no effect on pulmonary artery pressure, cardiac output, or pulse oxygen saturation measured during steady state exercise. There was no effect of sildenafil on mean power output during the time-trial. During high intensity cycle exercise in acute, moderate hypoxia pulmonary artery pressure is unaffected by sildenafil and does not appear to influence cardiovascular function or exercise performance.

Does altitude level of a prior time‐trial modify subsequent exercise performance in hypoxia and associated neuromuscular responses?

We examined the influence of prior time‐trials performed at different altitudes on subsequent exercise in moderate hypoxia and associated cardiometabolic and neuromuscular responses. In normobaric hypoxia (simulated altitude 2000 m; FiO2: 0.163), 10 healthy males performed (1) an incremental test to exhaustion (VO 2max_2000) and (2) a test to exhaustion at 80% of the power output associated to VO 2max_2000 for a reference time (947 ± 336 sec). Thereafter, two sessions were conducted in a randomized order: a cycle time‐trial corresponding to the reference time (TT 1) followed 22 min later (passive rest at 2000 m) by a 6‐min cycle time‐trial (TT 2). TT 1 was either performed at 2000 or 3500 m (FiO2: 0.135), while TT 2 was always performed at 2000 m. As expected, during TT 1, the mean power output (247 ± 42 vs. 227 ± 37 W; P < 0.001) was higher at 2000 than 3500 m. During TT 2, the mean power output (256 ± 42 vs. 252 ± 36 W) did not differ between conditions. Before and after TT 1, maximal isometric voluntary contraction torque in knee extensors (pooled conditions: −7.9 ± 8.4%; P < 0.01), voluntary activation (−4.1 ± 3.1%; P < 0.05), and indices of muscle contractility (peak twitch torque: −39.1 ± 11.9%; doublet torques at 100 Hz: −15.4 ± 8.9%; 10/100 Hz ratio: −25.8 ± 7.7%; all P < 0.001) were equally reduced at 2000 m or 3500 m. Irrespective of the altitude of TT 1, neuromuscular function remained similarly depressed after TT 1 both before and after TT 2 at 2000 m. A prior time‐trial performed at different altitude influenced to the same extent performance and associated cardiometabolic and neuromuscular responses during a subsequent exercise in moderate hypoxia.

High-altitude ancestry and hypoxia acclimation have distinct effects on exercise capacity and muscle phenotype in deer mice.

The hypoxic and cold environment at high altitudes requires that small mammals sustain high rates of O2 transport for exercise and thermogenesis while facing a diminished O2 availability. We used laboratory-born and -raised deer mice (Peromyscus maniculatus) from highland and lowland populations to determine the interactive effects of ancestry and hypoxia acclimation on exercise performance. Maximal O₂consumption (V̇o(2max)) during exercise in hypoxia increased after hypoxia acclimation (equivalent to the hypoxia at ∼4,300 m elevation for 6-8 wk) and was consistently greater in highlanders than in lowlanders. V̇o(2max) during exercise in normoxia was not affected by ancestry or acclimation. Highlanders also had consistently greater capillarity, oxidative fiber density, and maximal activities of oxidative enzymes (cytochrome c oxidase and citrate synthase) in the gastrocnemius muscle, lower lactate dehydrogenase activity in the gastrocnemius, and greater cytochrome c oxidase activity in the diaphragm. Hypoxia acclimation did not affect any of these muscle traits. The unique gastrocnemius phenotype of highlanders was associated with higher mRNA and protein abundances of peroxisome proliferator-activated receptor γ (PPARγ). Vascular endothelial growth factor (VEGFA) transcript abundance was lower in highlanders, and hypoxia acclimation reduced the expression of numerous genes that regulate angiogenesis and energy metabolism, in contrast to the observed population differences in muscle phenotype. Lowlanders exhibited greater increases in blood hemoglobin content, hematocrit, and wet lung mass (but not dry lung mass) than highlanders after hypoxia acclimation. Genotypic adaptation to high altitude, therefore, improves exercise performance in hypoxia by mechanisms that are at least partially distinct from those underlying hypoxia acclimation.

Genetic factors associated with exercise performance in atmospheric hypoxia.

Background and Objective‘Natural selection’ has been shown to have enriched the genomes of high-altitude native populations with genetic variants of advantage in this hostile hypoxic environment. In lowlanders who ascend to altitude, genetic factors may also contribute to the substantial interindividual variation in exercise performance noted at altitude. We performed a systematic literature review to identify genetic variants of possible influence on human hypoxic exercise performance, commenting on the strength of any identified associations.Criteria for considering studies for this reviewAll studies of the association of genetic factors with human hypoxic exercise performance, whether at sea level using ‘nitrogen dilution of oxygen’ (normobaric hypoxia), or at altitude or in low-pressure chambers (field or chamber hypobaric hypoxia, respectively) were sought for review.Search strategy for identification of studiesTwo electronic databases were searched (Ovid MEDLINE, Embase) up to 31 January 2014. We also searched the reference lists of relevant articles for eligible studies. All studies published in English were included, as were studies in any language for which the abstract was available in English.Data collection and analysisStudies were selected and data extracted independently by two reviewers. Differences regarding study inclusion were resolved through discussion. The quality of each study was assessed using a scoring system based on published guidelines for conducting and reporting genetic association studies.ResultsA total of 11 studies met all inclusion criteria and were included in the review. Subject numbers ranged from 20 to 1,931 and consisted of healthy individuals in all cases. The maximum altitude of exposure ranged from 2,690 to 8,848 m. The exercise performance phenotypes assessed were mountaineering performance (n = 5), running performance (n = 2), and maximum oxygen consumption ( dot{V} O2max) (n = 4). In total, 13 genetic polymorphisms were studied, four of which were associated with hypoxic exercise performance. The adenosine monophosphate deaminase (AMPD1) C34T (rs17602729), beta2-adrenergic receptor (ADRB2) Gly16Arg single nucleotide polymorphism (SNP) (rs1042713), and androgen receptor CAG repeat polymorphisms were associated with altitude performance in one study, and the angiotensin I-converting enzyme (ACE) insertion/deletion (I/D) (rs4646994) polymorphism was associated with performance in three studies. The median score achieved in the study quality analysis was 6 out of 10 for case–control studies, 8 out of 10 for cohort studies with a discrete outcome, 6 out of 9 for cohort studies with a continuous outcome, and 4.5 out of 8 for genetic admixture studies.ConclusionThe small number of articles identified in the current review and the limited number of polymorphisms studied in total highlights that the influence of genetic factors on exercise performance in hypoxia has not been studied in depth, which precludes firm conclusions being drawn. Support for the association between the ACE-I allele and improved high-altitude performance was the strongest, with three studies identifying a relationship. Analysis of study quality highlights the need for future studies in this field to improve the conduct and reporting of genetic association studies.Electronic supplementary materialThe online version of this article (doi:10.1007/s40279-015-0309-8) contains supplementary material, which is available to authorized users.

Systemic oxidative-nitrosative-inflammatory stress during acute exercise in hypoxia; implications for microvascular oxygenation and aerobic capacity.

Exercise performance in hypoxia may be limited by a critical reduction in cerebral and skeletal tissue oxygenation, although the underlying mechanisms remain unclear. We examined whether increased systemic free radical accumulation during hypoxia would be associated with elevated microvascular deoxygenation and reduced maximal aerobic capacity (V̇O2 max ). Eleven healthy men were randomly assigned single-blind to an incremental semi-recumbent cycling test to determine V̇O2 max in both normoxia (21% O2) and hypoxia (12% O2) separated by a week. Continuous-wave near-infrared spectroscopy was employed to monitor concentration changes in oxy- and deoxyhaemoglobin in the left vastus lateralis muscle and frontal cerebral cortex. Antecubital venous blood samples were obtained at rest and at V̇O2 max to determine oxidative (ascorbate radical by electron paramagnetic resonance spectroscopy), nitrosative (nitric oxide metabolites by ozone-based chemiluminescence and 3-nitrotyrosine by enzyme-linked immunosorbent assay) and inflammatory stress biomarkers (soluble intercellular/vascular cell adhesion1 molecules by enzyme-linked immunosorbent assay). Hypoxia was associated with increased cerebral and muscle tissue deoxygenation and lower V̇O2 max (P<0.05 versus normoxia). Despite an exercise-induced increase in oxidative-nitrosative-inflammatory stress, hypoxia per se did not have an additive effect (P>0.05 versus normoxia). Consequently, we failed to observe correlations between any metabolic, haemodynamic and cardiorespiratory parameters (P>0.05). Collectively, these findings suggest that altered free radical metabolism cannot explain the elevated microvascular deoxygenation and corresponding lower V̇O2 max in hypoxia. Further research is required to determine whether free radicals when present in excess do indeed contribute to the premature termination of exercise in hypoxia.

Effects of Beetroot Supplementation on Oxygen Consumption, Arterial Oxygen Saturation, and Exercise Performance in Hypoxia.

Effects of Beetroot Supplementation on Oxygen Consumption, Arterial Oxygen Saturation, and Exercise Performance in Hypoxia.

Cerebral oxygenation during the Richalet hypoxia sensitivity test and cycling time-trial performance in severe hypoxia

The Richalet hypoxia sensitivity test (RT), which quantifies the cardiorespiratory response to acute hypoxia during exercise at an intensity corresponding to a heart rate of ~130 bpm in normoxia, can predict susceptibility of altitude sickness. Its ability to predict exercise performance in hypoxia is unknown. Investigate: (1) whether cerebral blood flow (CBF) and cerebral tissue oxygenation (O2Hb; oxygenated hemoglobin, HHb; deoxygenated hemoglobin) responses during RT predict time-trial cycling (TT) performance in severe hypoxia; (2) if subjects with blunted cardiorespiratory responses during RT show greater impairment of TT performance in severe hypoxia. Thirteen men [27 ± 7 years (mean ± SD), Wmax: 385 ± 30 W] were evaluated with RT and the results related to two 15 km TT, in normoxia and severe hypoxia (FIO2 = 0.11). During RT, mean middle cerebral artery blood velocity (MCAv: index of CBF) was unaltered with hypoxia at rest (p > 0.05), while it was increased during normoxic (+22 ± 12 %, p < 0.05) and hypoxic exercise (+33 ± 17 %, p < 0.05). Resting hypoxia lowered cerebral O2Hb by 2.2 ± 1.2 μmol (p < 0.05 vs. resting normoxia); hypoxic exercise further lowered it to -7.6 ± 3.1 μmol below baseline (p < 0.05). Cerebral HHb, increased by 3.5 ± 1.8 μmol in resting hypoxia (p < 0.05), and further to 8.5 ± 2.9 μmol in hypoxic exercise (p < 0.05). Changes in CBF and cerebral tissue oxygenation during RT did not correlate with TT performance loss (R = 0.4, p > 0.05 and R = 0.5, p > 0.05, respectively), while tissue oxygenation and SaO2 changes during TT did (R = -0.76, p < 0.05). Significant correlations were observed between SaO2, MCAv and HHb during RT (R = -0.77, -0.76 and 0.84 respectively, p < 0.05 in all cases). CBF and cerebral tissue oxygenation changes during RT do not predict performance impairment in hypoxia. Since the changes in SaO2 and brain HHb during the TT correlated with performance impairment, the hypothesis that brain oxygenation plays a limiting role for global exercise in conditions of severe hypoxia remains to be tested further.

Effect of end-tidal CO2 clamping on cerebrovascular function, oxygenation, and performance during 15-km time trial cycling in severe normobaric hypoxia: the role of cerebral O2 delivery

During heavy exercise, hyperventilation-induced hypocapnia leads to cerebral vasoconstriction, resulting in a reduction in cerebral blood flow (CBF). A reduction in CBF would impair cerebral O2 delivery and potentially account for reduced exercise performance in hypoxia. We tested the hypothesis that end-tidal Pco2 (PETCO2) clamping in hypoxic exercise would prevent the hypocapnia-induced reduction in CBF during heavy exercise, thus improving exercise performance. We measured PETCO2, middle cerebral artery velocity (MCAv; index of CBF), prefrontal cerebral cortex oxygenation (cerebral O2Hb; index of cerebral oxygenation), cerebral O2 delivery (DO2), and leg muscle oxygenation (muscle O2Hb) in 10 healthy men (age 27 ± 7 years; VO2max 63.3 ± 6.6 mL/kg/min; mean ± SD) during simulated 15-km time trial cycling (TT) in normoxia and hypoxia (FIO2 = 0.10) with and without CO2 clamping. During exercise, hypoxia elevated MCAv and lowered cerebral O2Hb, cerebral DO2, and muscle O2Hb (P < 0.001). CO2 clamping elevated PETCO2 and MCAv during exercise in both normoxic and hypoxic conditions (P < 0.001 and P = 0.024), but had no effect on either cerebral and muscle O2Hb (P = 0.118 and P = 0.124). Nevertheless, CO2 clamping elevated cerebral DO2 during TT in both normoxic and hypoxic conditions (P < 0.001). CO2 clamping restored cerebral DO2 to normoxic values during TT in hypoxia and tended to have a greater effect on TT performance in hypoxia compared to normoxia (P = 0.097). However, post hoc analysis revealed no effect of CO2 clamping on TT performance either in normoxia (P = 0.588) or in hypoxia (P = 0.108). Our findings confirm that the hyperventilation-induced hypocapnia and the subsequent drop in cerebral oxygenation are unlikely to be the cause of the reduced endurance exercise performance in hypoxia.

Effects of garlic consumption on physiological variables and performance during exercise in hypoxia

Exposure to hypoxia results in vasoconstriction of the pulmonary vasculature (HPV) leading to pulmonary hypertension (HPH) and reductions in blood oxygen saturation and exercise performance. Alleviation of HPV and HPH via vasodilators has been shown to improve blood oxygen saturation and exercise performance in hypoxia. Garlic has been shown to reduce HPV and HPH in rats and has been suggested to have ergogenic effects in hypoxic exercise. We compared the effects of 7 days of supplementation with garlic and placebo on peripheral blood pressures, blood oxygen saturation, heart rate, oxygen consumption, and time to exhaustion during a progressive exercise test to exhaustion in humans under hypoxia (PIO2 ∼ 88 Torr). No significant differences were observed between treatments regarding oxygen consumption, exercise or resting peripheral blood pressures, blood oxygen saturation, heart rates, or exercise time to exhaustion. These results do not support garlic consumption as a method for improving peripheral blood pressure, maximal oxygen consumption, blood oxygen saturation, exercising heart rate, heart rate response, or exercise performance in hypoxia.

Commentaries on Viewpoint: Evidence that reduced skeletal muscle recruitment explains the lactate paradox during exercise at high altitude

to the editor: Noakes ([5][1]) and other authors have proposed that central motor command (CMC) and, consequently, exercise performance in hypoxia is determined by the following. 1 ) By simple negative feedback ([1][2], [2][3]) or complex feedback/feedforward ([4][4]) subconscious homeostatic

Preacclimatization in simulated altitudes

Acute exposure to high altitude provokes the development of mountain illnesses and decrease of exercise performance. Thus, sufficient acclimatization is of utmost importance for mountaineers, trekkers, and athletes performing at high altitude. The main purpose of this paper was to review existing studies and observations on the effectiveness of preacclimatization at simulated altitude. A PubMed search has been performed and preliminary observations from our laboratory have been included. Although some beneficial effects have been demonstrated, it is not possible to draw firm conclusions from the few available studies dealing with the effects of preacclimatization at simulated altitude on the reduction of acute mountain sickness (AMS) incidence and performance loss at high altitude. For the present, 1-4 h of daily exposures for 1-5 weeks to simulated altitudes of about 4,000 m seem to initiate ventilatory and autonomous nervous system adaptations to high altitude with the potential to reduce AMS development. At least for protocols of short duration, rest during hypoxic exposures seems to be similarly effective as exercise. For the more prolonged protocols, exercise may be included to enhance exercise performance in hypoxia.

Prolyl hydroxylase inhibitor treatment confers whole‐animal hypoxia tolerance

Recently a family of O(2)-dependent prolyl hydroxylase domain-containing enzymes (PHD) has been identified as a cellular oxygen-sensing mechanism. Reduced prolyl hydroxylase activity initiates a signalling cascade that includes the accumulation, as well as the activation, of hypoxia-inducible factor (HIF-1alpha). In turn the transcription factor HIF-1alpha, and other targets of the PHD, elicit a myriad of incompletely understood cellular responses. In these studies we have tested: (1) whether a small-molecule prolyl hydroxylase inhibitor (PHI) can effectively activate the oxygen-sensing pathway when administered systemically to mice, and (2) whether the activation of the PHD signalling pathway at the cellular level results in whole-animal hypoxic tolerance. Mice received daily injections of the PHI, ethyl-3,4 dihydroxybenzoate (EDHB, 100-250 mg kg(-1)) or vehicle. Tissue levels of HIF-1alpha and the serum levels of the HIF-inducible gene, erythropoietin (EPO), were measured to evaluate PHD-pathway activation. To evaluate hypoxic tolerance, the endurance and survival ability of these animals was tested in sublethal (8% O(2)) and lethal hypoxia (5% O(2)) respectively. Systemic treatment of mice with the PHD inhibitor, EDHB, leads to elevated levels of HIF-1alpha in liver and HIF-inducible EPO in serum, indicating activation of the cellular oxygen-sensing pathway. Animals treated with EDHB display significantly increased viability and enhanced exercise performance in hypoxia. These results demonstrate a novel pharmacological strategy to induce hypoxic tolerance and are the first to demonstrate that the activation of the PHD oxygen-sensing pathway at the cellular level is sufficient to produce a hypoxic-tolerant phenotype at the physiological level of the whole animal.

Exercise performance in hypoxia after novel erythropoiesis stimulating protein treatment

Maximal aerobic power at high altitude (<4000 m) does not increase with altitude acclimatization. In order to investigate the isolated effects of increased arterial oxygen content (CaO2) on maximal oxygen uptake (VO2max) in hypoxia, we studied 10 subjects during exercise in acute exposure to 12.6% O2 before and after novel erythropoiesis stimulating protein (NESP) induced increases in CaO2. Over a period of 1 month, weekly NESP treatment increased resting hemoglobin (Hb) from 13.8+/-0.9 to 16.2+/-0.5 g/dL, hematocrit from 42.1+/-0.6% to 49.0+/-1.5%, and CaO2 from 189.7+/-3.0 to 218.6+/-5.7 mL/L. At maximal exercise CaO2 was increased from 172.3+/-3.7 to 191.5+/-3.8 mL/L with NESP treatment, and although maximal heart rate was similar in both conditions (178.4+/-2.6 and 180.9+/-2.5 b.p.m.) VO2max remained unaltered, the values being 3.12+/-2.0 and 3.12+/-2.0, before and after NESP treatment, respectively. NESP-injections in human subjects causes Hb and accordingly CaO2 to increase both in normoxia and hypoxia. Despite increases in CaO2 at maximal exercise in hypoxia VO2max is not increased.