Live high - train low altitude camps can enhance endurance power at sea level by 1-2% (Levine & Stray-Gunderson, 1997). More convenient methods to simulate altitude exposure are now available, but their effects on performance are less well characterized. In this study, we investigated intermittent hypoxic training (IHT) using an Hypoxicator, a device that produces oxygen-depleted air that athletes breathe intermittently through masks in a small group at a central venue. Twelve highly-competitive, male cyclists and multi-sport athletes (IHT group) underwent IHT in two, four-week bouts separated by eight weeks. Bout one consisted of 20 one-hour exposures and bout two 18 exposures where normal and low-oxygenated air was breathed in alternating five-minute intervals. The percentage of oxygen inhaled by the subjects was adjusted to produce an oxygen saturation of the blood of 88-92% in the first week of the study, decreasing to 76-80% (equivalent to an altitude of approximately 6000m) in the final week. A control group of 13 similar athletes did not use the Hypoxicator. Performance trials and blood tests were at four-week intervals; there were 3 trials (familiarization and reliability) before use of the Hypoxicator, 3 trials after to determine the effect of simulated altitude, then a second four-week exposure and one more trial. The measures of performance were mean power in a 16-km time trial on a Kingcycle ergometer (IHT group only) and power in a lactate-threshold test at 3 mmol/L above baseline (both groups). The measures from the blood tests were haemoglobin and haematocrit. There was a gradual but erratic improvement in performance in the time trial and lactate threshold tests over the course of the study in both groups, indicating an improvement through training. Relative to the last baseline test (Trial 3), the IHT group showed a 0.6% decrease in mean power over and above the effect of training in the 16-km time trial in Trial 4, nine days after last use of IHT. There was a 0.3% increase in mean power independent of the training effect in Trial 7, after the second round of altitude exposure. Uncertainty in these changes in performance was ±3.5% (95% confidence interval). The changes in lactate threshold in trials 4 and 7 indicate a possible improvement as a result of IHT exposure. Uncertainty in these changes was ±4.0%. There were negligible changes in the haemoglobin and hematocrit of either group at any time. There was small evidence of high responders, who were probably subjects with the DD genotype for the angiotensin converting enzyme gene. The time exposed to IHT had no bearing on performance and there was no evidence "peak" in results at either four or eight weeks after exposure to IHT. In summary, four weeks of IHT exposure probably resulted in a trivial effect on 16-km time-trial performance and the effort-independent measures provided no further clear-cut evidence of a performance improvement.

Lors de variations de PO2 et PCO2, différents mécanismes se mettent en place afin demaintenir l’oxygénation des tissus, notamment au niveau du métabolisme et de la ventilation. En casde stimulation hypoxique ou hypercapnique, on observe alors une réponse ventilatoire, caractériséepar une augmentation progressive de la ventilation. Parmi les facteurs qui influencent la réponse àl’hypoxie, on trouve l’érythropoïétine (Epo) qui, en plus de son rôle dans l’érythropoïèse, possèded’autres rôles, notamment au sein du système nerveux central. Cette thèse présente l’étude del’implication de l’Epo et de différents systèmes de neurotransmission dans les réponses ventilatoiresà l’hypoxie (RVH) et à l’hypercapnie (RVHc).Nous avons alors pu mettre en évidence l’implication du NO, du glutamate et de la sérotonine dansla RVH et dans l’acclimatation ventilatoire à une hypoxie prolongée (VAH) chez un modèle de sourisanémique déficient en Epo (Epo-TAgh) et un animal adapté à la vie en altitude, la plateau Pika. Nousavons ensuite étudié l’impact de la déficience en Epo sur la RVHc, et nous avons confirmé que l’Epon’était pas nécessaire à l’obtention de la RVHc, tout en mettant en évidence un rôle de l’Epo sur lepatron ventilatoire et sur l’implication de certaines structures du système nerveux central dans lamise en place de cette réponse. Une étude en parallèle sur les femelles a permis de mettre enévidence que le cycle oestral n’était pas impliqué dans les réponses ventilatoires mais qu’il semble yavoir une interaction entre l’Epo et les hormones sexuelles femelles dans la RVH et la RVHc. Enfin,différentes expériences réalisées lors de collaborations (Chili, Canada) ont permis d’étudier les effetsde l’Epo sur les chémorécepteurs centraux et périphériques dans la mise en place des réponsesventilatoires.In fine, ces différentes expériences ont permis de préciser les différents facteurs impliqués dans lamise en place des réponses ventilatoires à l’hypoxie et à l’hypercapnie, ce qui pourrait aider par lasuite à mieux comprendre les modifications respiratoires induites par des pathologiques liées àl’anémie ou l’exposition prolongée à l’altitude. / When PO2 and PCO2 are modified, various mechanisms are being established to maintaintissue oxygenation, such as ventilation and metabolism adaptations. In case of hypoxia orhypercapnia stimulation, we observed a ventilatory response, characterized by an increase in minuteventilation. Among the factors involved in the hypoxic response, Epo plays a key role. In addition toits role in erythropoiesis, Epo has other functions, especially in the central nervous system. Thisthesis presents the study of Epo involvement in the ventilatory responses to hypoxia (HVR) andhypercapnia (HcVR).We demonstrate the involvement of NO, glutamate and serotonin in the HVR and in acclimatizationto sustained hypoxia (VAH) in Epo deficient mice (Epo-TAgh) and in an animal adapted to highaltitude, the plateau Pika. Then we studied the impact of Epo-deficiency on HcVR and confirmed thatEpo is not mandatory to obtained HcVR but we demonstrate that Epo can modulate the ventilatorypattern and central nervous system structures involvement in this response. During this study, wealso demonstrate that in female mice, estrous cycle is not involved in HVR or HcVR but it seems thatthere is an interaction between Epo and female sexual hormones in these responses. Finally, someexperiments in collaboration with different countries (Chile, Canada) allowed us to study the effectsof Epo on peripheral and central chemoreceptors during HVR and HcVR.In fine, these experiments allows us to specify the factors involved in ventilatory responses tohypoxia and hypercapnia, which could be helpful to better understand respiratory pathologies suchas anemia or pathologies associated with high altitude.

Changes to the metabolism of the cardiomyocyte are driven by complex signaling pathways in order to adjust to stress. For instance, HIF-1α is classically known to upregulate glycolytic metabolism to compensate for oxygen deficiency. Other important effects upon glucose metabolism, which we investigate here more extensively, were also observed. Hearts derived from mice with the cardiac-restricted expression of a stabilized form of HIF-1α are remarkably ischemia stress-tolerant. Here, stable isotope-resolved metabolomic analyses were utilized to investigate glucose cardiometabolism remodeling by HIF-1αduring ischemia. We found that 13C-lactate accumulation was significantly elevated in HIF-1α expressing hearts while paradoxically glycogen was maintained to a remarkable extent during an ischemic time course. These findings suggested an unexpected source of glucose in HIF-1α hearts during global ischemia. Accordingly, the presence of gluconeogenesis in hearts was evaluated. Indeed, gluconeogenic intermediates (i.e. m+3) including glucose-6-phosphate [m+3], fructose-6-phosphate [m+3], and fructose 1,6-bisphosphate [m+3] were observed at significantly elevated levels in the ischemic HIF-1α heart. Collectively, these data establish the surprising finding that HIF-1α supports active gluconeogenesis in the heart during ischemia. As less is known regarding the effects of CTRP3 we first tested whether CTRP3 overexpression would protect the ischemic heart. Our data indicate that CTRP3 failed to confer ischemic tolerance in heart ex vivo. However,we were able to show that CTRP3 protected the liver from lipid-induced stress and prevented hepatic lipid accumulation. To further investigate the mechanisms of hepatic protective effect mediated by CTRP3, we identified the receptor and established that CTRP3 increases oxygen consumption in response to lipid overloaded. Lysosomal-associated membrane protein 1 (LAMP-1), In summary, these data indicate that targeted metabolic rearrangements within cardiomyocyte/hepatocyte holds promise for the alleviation of common pathological conditions.

Ascent to altitude presents a significant challenge to the human body. Specifically, it is associated with an increased ventilation and pulmonary vasoconstriction. In healthy subjects these are related such that a high ventilatory drive is associated with blunted pulmonary vasoconstriction. Adults born prematurely and given supplemental oxygen at birth have a blunted ventilatory response to hypoxia. We hypothesized that the hypoxic ventilatory and pulmonary vasoconstrictor responses would be unrelated following perinatal supplemental oxygen exposure. To test our hypothesis, we used a well-established rat model of 80% O2 (80%) exposure for 14 days post-natally, with 21% O2 exposure as a control (21%). We assessed the ventilatory response to graded hypoxia using barometric plethysmography 6-9 months post hyperoxia exposure. The left and right ventricles were catheterized to evaluate the hemodynamic response to 10 minutes of 12% O2 (hypoxia). To our surprise we found that 80% animals did not demonstrate a depressed ventilatory response to hypoxia. However, these animals experienced increased right ventricular systolic pressure in response to 12% O2. An increase in cardiac output was the primary driving force behind the increase in right ventricular end systolic pressure, not an increase in vascular resistance. We found no relationship between the hypoxic ventilatory drive and right ventricular pressure. In 21% animals exposed to hypoxia, the increase in right ventricular pressure was driven primarily by vasoconstriction and, as previous studies have shown, there was a relationship between the ventilatory and pressure responses. These data suggest that neonatal supplemental oxygen alters the hemodynamic response to hypoxia, possibly through enhanced sympathetic drive. The relationship between ventilation and pulmonary pressure may not translate to individuals born prematurely.

No description available.

When spontaneous breathing (SB) is allowed during mechanical ventilation (MV), atelectatic lung areas are recruited and oxygenation improves thereby. Whether unsupported SB at its natural pattern (without PEEP and at low pressure/small tidal volume) equally recruits and improves oxygenation, and if so by which mechanism, has not been studied. A porcine lung collapse model was designed to study this question. The cardiac output dependency of the pulmonary shunt was investigated with healthy lungs and with major shunt (during one-lung ventilation) and with SB, MV and continuous positive airway pressure (CPAP). The hypoxic pulmonary vasoconstriction (HPV) was blocked with sodium nitroprusside (SNP) to see whether HPV is the only mechanism available for ventilation/perfusion (VA/Q) matching during MV and SB. In all experiments, respiratory rate and tidal volume during MV were matched to SB. Oxygenation was assessed by serial blood gas measurements, recruitment by thoracic CTs; pulmonary shunt was assessed by multiple inert gas elimination or venous admixture. SB attained better oxygenation and lower pulmonary shunt compared with MV, although it did not recruit collapsed lung. Pulmonary shunt did not correlate with cardiac output during SB, whereas a correlation was found during MV and CPAP. With blocked HPV, pulmonary shunt was considerably lower during SB than MV. In conclusion, SB improves VA/Q matching as compared with MV, even when no recruitment occurs. In contrast to MV and CPAP, cardiac output has no major effect on pulmonary shunt during SB. The improved VA/Q matching during SB despite a blocked HPV might indicate the presence of a SB-specific mechanism that improves pulmonary blood flow redistribution towards ventilated lung regions independent of or supplementary to HPV.

Strong evidence exists to support the use of a continuous (>8hr/day) hypoxic stimulus (either geographical altitude or simulated hypoxia) for enhancing the physical performance of endurance athletes. However, evidence supporting the use of acutely intermittent hypoxia (<1hr/day) for enhancing performance is less clear. The purpose of this study was to determine the effect of acutely intermittent hypoxic exposure on physiological and physical performance measures in team sport athletes. Using a single-blind controlled design, 14 trained basketball players (HYP = 7, CON = 7) were subjected to 15 days of intermittent hypoxia or normoxia. Each exposure was 37 minutes in duration (four cycles of 7min on, 3min off) and achieved using a nitrogen dilution device (Airo Ltd, Auckland, NZ). Prescribed peripheral oxygen saturation levels (SpO2) were maintained using an automatic biofeedback system and were progressively decreased from 86-89% on Day 1 to 75-78% on Day 15. A range of physiological measures and performance tests were conducted seven and two days before, and ten days after the intervention. The tests were: an incremental treadmill test to establish peak oxygen consumption ( peak) and running economy (RE), Yo-Yo Intermittent Recovery Test (YYIRT), and the Repeated High-Intensity Endurance Test (RHIET). Whole-blood samples were taken to assess a range of haematological measures. At 10 days post-intervention the HYP group, relative to the CON group, exhibited the following percent changes (±90% confidence limits, CL), and effect sizes (ES; ±90% CL); YYIRT running speedpeak (4.8; ± 1.6%, ES: 1.0 ± 0.4; benefit almost certain), RHIET total sprint time (-3.5; ± 1.6%; ES: -0.4 ± 0.2; benefit very likely), RHIET slowest sprint time (-5.0; ± 2.4%; ES: -0.5 ± 0.2; benefit very likely), soluble transferrin receptor (9.2; ± 10.1%; ES: 0.3 ± 0.3; benefit possible) running economy (11km.hr-1) (-9.0; ± 9.7%; ES: -0.7 ± 0.7; benefit likely, probable), and running economy (13km.hr-1) (-8.2; ± 6.9%; ES: -0.7 ± 0.5; benefit likely, probable). Changes to running economy (9km.hr-1), peak, maximum heart rate and lactate and all other blood measures were unclear. In conclusion, acutely intermittent hypoxia resulted in worthwhile changes in physical performance of trained basketball players in tests relevant to competition. However, the lack of clear change in physiological and haematological measures makes it difficult to determine the underlying mechanism for such enhancement.

Strong evidence exists to support the use of a continuous (>8hr/day) hypoxic stimulus (either geographical altitude or simulated hypoxia) for enhancing the physical performance of endurance athletes. However, evidence supporting the use of acutely intermittent hypoxia (<1hr/day) for enhancing performance is less clear. The purpose of this study was to determine the effect of acutely intermittent hypoxic exposure on physiological and physical performance measures in team sport athletes. Using a single-blind controlled design, 14 trained basketball players (HYP = 7, CON = 7) were subjected to 15 days of intermittent hypoxia or normoxia. Each exposure was 37 minutes in duration (four cycles of 7min on, 3min off) and achieved using a nitrogen dilution device (Airo Ltd, Auckland, NZ). Prescribed peripheral oxygen saturation levels (SpO2) were maintained using an automatic biofeedback system and were progressively decreased from 86-89% on Day 1 to 75-78% on Day 15. A range of physiological measures and performance tests were conducted seven and two days before, and ten days after the intervention. The tests were: an incremental treadmill test to establish peak oxygen consumption ( peak) and running economy (RE), Yo-Yo Intermittent Recovery Test (YYIRT), and the Repeated High-Intensity Endurance Test (RHIET). Whole-blood samples were taken to assess a range of haematological measures. At 10 days post-intervention the HYP group, relative to the CON group, exhibited the following percent changes (±90% confidence limits, CL), and effect sizes (ES; ±90% CL); YYIRT running speedpeak (4.8; ± 1.6%, ES: 1.0 ± 0.4; benefit almost certain), RHIET total sprint time (-3.5; ± 1.6%; ES: -0.4 ± 0.2; benefit very likely), RHIET slowest sprint time (-5.0; ± 2.4%; ES: -0.5 ± 0.2; benefit very likely), soluble transferrin receptor (9.2; ± 10.1%; ES: 0.3 ± 0.3; benefit possible) running economy (11km.hr-1) (-9.0; ± 9.7%; ES: -0.7 ± 0.7; benefit likely, probable), and running economy (13km.hr-1) (-8.2; ± 6.9%; ES: -0.7 ± 0.5; benefit likely, probable). Changes to running economy (9km.hr-1), peak, maximum heart rate and lactate and all other blood measures were unclear. In conclusion, acutely intermittent hypoxia resulted in worthwhile changes in physical performance of trained basketball players in tests relevant to competition. However, the lack of clear change in physiological and haematological measures makes it difficult to determine the underlying mechanism for such enhancement.

Live high - train low altitude camps can enhance endurance power at sea level by 1-2% (Levine & Stray-Gunderson, 1997). More convenient methods to simulate altitude exposure are now available, but their effects on performance are less well characterized. In this study, we investigated intermittent hypoxic training (IHT) using an Hypoxicator, a device that produces oxygen-depleted air that athletes breathe intermittently through masks in a small group at a central venue. Twelve highly-competitive, male cyclists and multi-sport athletes (IHT group) underwent IHT in two, four-week bouts separated by eight weeks. Bout one consisted of 20 one-hour exposures and bout two 18 exposures where normal and low-oxygenated air was breathed in alternating five-minute intervals. The percentage of oxygen inhaled by the subjects was adjusted to produce an oxygen saturation of the blood of 88-92% in the first week of the study, decreasing to 76-80% (equivalent to an altitude of approximately 6000m) in the final week. A control group of 13 similar athletes did not use the Hypoxicator. Performance trials and blood tests were at four-week intervals; there were 3 trials (familiarization and reliability) before use of the Hypoxicator, 3 trials after to determine the effect of simulated altitude, then a second four-week exposure and one more trial. The measures of performance were mean power in a 16-km time trial on a Kingcycle ergometer (IHT group only) and power in a lactate-threshold test at 3 mmol/L above baseline (both groups). The measures from the blood tests were haemoglobin and haematocrit. There was a gradual but erratic improvement in performance in the time trial and lactate threshold tests over the course of the study in both groups, indicating an improvement through training. Relative to the last baseline test (Trial 3), the IHT group showed a 0.6% decrease in mean power over and above the effect of training in the 16-km time trial in Trial 4, nine days after last use of IHT. There was a 0.3% increase in mean power independent of the training effect in Trial 7, after the second round of altitude exposure. Uncertainty in these changes in performance was ±3.5% (95% confidence interval). The changes in lactate threshold in trials 4 and 7 indicate a possible improvement as a result of IHT exposure. Uncertainty in these changes was ±4.0%. There were negligible changes in the haemoglobin and hematocrit of either group at any time. There was small evidence of high responders, who were probably subjects with the DD genotype for the angiotensin converting enzyme gene. The time exposed to IHT had no bearing on performance and there was no evidence "peak" in results at either four or eight weeks after exposure to IHT. In summary, four weeks of IHT exposure probably resulted in a trivial effect on 16-km time-trial performance and the effort-independent measures provided no further clear-cut evidence of a performance improvement.

Multicellular organisms typically depend on O₂ for energy production to maintain normal cellular function, and even brief periods of O₂ deprivation may have fatal consequences. The aqueous environment is prone to changes in ambient water O₂ tension (PO₂) and thus the ability of fish to sense changes in water PO₂ and to elicit appropriate physiological responses is essential for their survival. Studies on fish O₂ chemoreception have identified neuroepithelial cells (NECs), which are characterized as having dense-cored vesicles containing serotonin (5-HT), as peripheral O₂ chemoreceptors. Upon exposure to hypoxia, isolated and cultured NECs in vitro depolarize, likely resulting in neurotransmitter release. However, to date there is no evidence that NECs are activated by hypoxia in vivo to initiate physiological responses such as the hypoxic ventilatory response (HVR), which is the focus of this thesis. Initial findings demonstrated that larval zebrafish fine-tune the HVR as early as 4 days post fertilization (dpf) and by 7 dpf, the HVR aids in O₂ uptake under hypoxic conditions. In addition, the HVR is multiphasic, with an initiation phase followed by a decline phase that gradually stabilizes above normoxic baseline values (Chapter 2). In the absence of tools to probe the hypoxia sensitivity of NECs in vivo, research focused on Merkel-like cells (MLCs), a newly proposed O₂ chemoreceptor in larval zebrafish. Using in vivo calcium imaging it was shown that MLCs are stimulated by hypoxia. Data suggest that MLCs are responsible for the initiation phase of the HVR, while peripheral sensory neurons (PSNs)/peripheral sensory ganglia (PSG) that innervate MLCs play a more important role in reducing ventilation during the decline phase of the HVR (Chapter 4). Attempts at identifying the putative neurotransmitter(s) involved in the O₂ signal transduction pathway revealed that adrenaline (AD), serotonin (5-HT), and dopamine (DA) are probable candidates (Chapter 4), though the presence of AD and DA within MLCs is yet to be confirmed. In addition, 5-HT likely plays a role in the central nervous system (CNS), integrating peripheral signals resulting in the final HVR (Chapter 3). Taken together, this thesis provides the first evidence of putative O₂ chemoreceptors responding to hypoxia in vivo and thus significantly advances models for O₂ signal transduction in larval zebrafish.