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Hypoxia refers to environmental or clinical settings that potentially threaten tissue oxygen homeostasis. One unique aspect of skeletal muscle is that, in addition to hypoxia, oxygen balance in this tissue may be further compromised when exercise is superimposed on hypoxia. This review focuses on the cellular and molecular responses of human skeletal muscle to acute and chronic hypoxia, with emphasis on physical exercise and training. Based on published work, it is suggested that hypoxia does not appear to promote angiogenesis or to greatly alter oxidative enzymes in skeletal muscle at rest. Although the HIF-1 pathway in skeletal muscle is still poorly documented, emerging evidence suggests that muscle HIF-1 signaling is only activated to a minor degree by hypoxia. On the other hand, combining hypoxia with exercise appears to improve some aspects of muscle O₂ transport and/or metabolism.

Chronic mountain sickness is a maladaptive syndrome that affects individuals living permanently at high altitude and is characterized primarily by excessive erythrocytosis (EE). Recent results concerning the impact of EE in Andean highlanders on clotting and the possible promotion of hypercoagulability, which can lead to thrombosis, were contradictory. We assessed the coagulation profiles of Andeans highlanders with and without excessive erythrocytosis (EE+ and EE−). Blood samples were collected from 30 EE+ and 15 EE− in La Rinconada (Peru, 5100–5300 m a.s.l.), with special attention given to the sampling pre‐analytical variables. Rotational thromboelastometry tests were performed at both native and normalized (40%) haematocrit using autologous platelet‐poor plasma. Thrombin generation, dosages of clotting factors and inhibitors were measured in plasma samples. Data were compared between groups and with measurements performed at native haematocrit in 10 lowlanders (LL) at sea level. At native haematocrit, in all rotational thromboelastometry assays, EE+ exhibited hypocoagulable profiles (prolonged clotting time and weaker clot strength) compared with EE− and LL (all P < 0.01). At normalized haematocrit, clotting times were normalized in most individuals. Conversely, maximal clot firmness was normalized only in FIBTEM and not in EXTEM/INTEM assays, suggesting abnormal platelet activity. Thrombin generation, levels of plasma clotting factors and inhibitors, and standard coagulation assays were mostly normal in all groups. No highlanders reported a history of venous thromboembolism based on the dedicated survey. Collectively, these results indicate that EE+ do not present a hypercoagulable profile potentially favouring thrombosis. What is the central question of this study? Are Andean highlanders with excessive erythrocytosis (EE+) exhibiting a hypercoagulable profile compared with highlanders without erythrocytosis (EE−) and lowlanders (LL)? What is the main finding and its importance? Despite normal plasma coagulation (thrombinography and levels of clotting factors and inhibitors), EE+ exhibited a hypocoagulable rotational thromboelastometry profile (prolonged clotting time and weaker clot strength) compared with EE− and LL. In EE+, haematocrit normalization at 40% corrected maximal clot firmness in rotational thromboelastometry FIBTEM tests, but not in EXTEM and INTEM tests, suggesting that platelets play a role in the native hypocoagulable profile.

This study investigated the changes in cerebral near-infrared spectroscopy (NIRS) signals, cerebrovascular and ventilatory responses to hypoxia and CO2 during altitude exposure. At sea level (SL), after 24 hours and 5 days at 4,350 m, 11 healthy subjects were exposed to normoxia, isocapnic hypoxia, hypercapnia, and hypocapnia. The following parameters were measured: prefrontal tissue oxygenation index (TOI), oxy- (HbO2), deoxy- and total hemoglobin (HbTot) concentrations with NIRS, blood velocity in the middle cerebral artery (MCAv) with transcranial Doppler and ventilation. Smaller prefrontal deoxygenation and larger ΔHbTot in response to hypoxia were observed at altitude compared with SL (day 5: ΔHbO2−0.6±1.1 versus −1.8±1.3 μmol/cmper mm Hg and ΔHbTot 1.4±1.3 versus 0.7±1.1 μmol/cm per mm Hg). The hypoxic MCAv and ventilatory responses were enhanced at altitude. Prefrontal oxygenation increased less in response to hypercapnia at altitude compared with SL (day 5: ΔTOI 0.3±0.2 versus 0.5±0.3% mm Hg). The hypercapnic MCAv and ventilatory responses were decreased and increased, respectively, at altitude. Hemodynamic responses to hypocapnia did not change at altitude. Short-term altitude exposure improves cerebral oxygenation in response to hypoxia but decreases it during hypercapnia. Although these changes may be relevant for conditions such as exercise or sleep at altitude, they were not associated with symptoms of acute mountain sickness.

Mont Blanc, the summit of Western Europe, is a popular but demanding high-altitude ascent. Drug use is thought to be widespread among climbers attempting this summit, not only to prevent altitude illnesses, but also to boost physical and/or psychological capacities. This practice may be unsafe in this remote alpine environment. However, robust data on medication during the ascent of Mont Blanc are lacking. Individual urine samples from male climbers using urinals in mountain refuges on access routes to Mont Blanc (Goûter and Cosmiques mountain huts) were blindly and anonymously collected using a hidden automatic sampler. Urine samples were screened for a wide range of drugs, including diuretics, glucocorticoids, stimulants, hypnotics and phosphodiesterase 5 (PDE-5) inhibitors. Out of 430 samples analyzed from both huts, 35.8% contained at least one drug. Diuretics (22.7%) and hypnotics (12.9%) were the most frequently detected drugs, while glucocorticoids (3.5%) and stimulants (3.1%) were less commonly detected. None of the samples contained PDE-5 inhibitors. Two substances were predominant: the diuretic acetazolamide (20.6%) and the hypnotic zolpidem (8.4%). Thirty three samples were found positive for at least two substances, the most frequent combination being acetazolamide and a hypnotic (2.1%). Based on a novel sampling technique, we demonstrate that about one third of the urine samples collected from a random sample of male climbers contained one or several drugs, suggesting frequent drug use amongst climbers ascending Mont Blanc. Our data suggest that medication primarily aims at mitigating the symptoms of altitude illnesses, rather than enhancing performance. In this hazardous environment, the relatively high prevalence of hypnotics must be highlighted, since these molecules may alter vigilance.

As a consequence to hypobaric hypoxic exposure skeletal muscle atrophy is often reported. The underlying mechanism has been suggested to involve a decrease in protein synthesis in order to conserve O(2). With the aim to challenge this hypothesis, we applied a primed, constant infusion of 1-(13)C-leucine in nine healthy male subjects at sea level and subsequently at high-altitude (4559 m) after 7-9 days of acclimatization. Physical activity levels and food and energy intake were controlled prior to the two experimental conditions with the aim to standardize these confounding factors. Blood samples and expired breath samples were collected hourly during the 4 hour trial and vastus lateralis muscle biopsies obtained at 1 and 4 hours after tracer priming in the overnight fasted state. Myofibrillar protein synthesis rate was doubled; 0.041±0.018 at sea-level to 0.080±0.018%⋅hr(-1) (p<0.05) when acclimatized to high altitude. The sarcoplasmic protein synthesis rate was in contrast unaffected by altitude exposure; 0.052±0.019 at sea-level to 0.059±0.010%⋅hr(-1) (p>0.05). Trends to increments in whole body protein kinetics were seen: Degradation rate elevated from 2.51±0.21 at sea level to 2.73±0.13 µmol⋅kg(-1)⋅min(-1) (p = 0.05) at high altitude and synthesis rate similar; 2.24±0.20 at sea level and 2.43±0.13 µmol⋅kg(-1)⋅min(-1) (p>0.05) at altitude. We conclude that whole body amino acid flux is increased due to an elevated protein turnover rate. Resting skeletal muscle myocontractile protein synthesis rate was concomitantly elevated by high-altitude induced hypoxia, whereas the sarcoplasmic protein synthesis rate was unaffected by hypoxia. These changed responses may lead to divergent adaptation over the course of prolonged exposure.

This study tested the effects of \"living high-training low\" (Hi-Lo) on aerobic performance and economy of work in elite athletes. Forty endurance athletes (cross-country skiers, swimmers, runners) performed 13-18 consecutive days of training at 1,200 m altitude, by sleeping at 1,200 m (LL, n = 20) or in hypoxic rooms with 5-6 nights at 2,500 m followed by 8-12 nights at 3,000-3,500 m (HL, n = 20). The athletes were evaluated before (pre-), one (post-1) and 15 days (post-15) after Hi-Lo. Economy was assessed from two sub-maximal tests, one non-specific (cycling) and one specific (running or swimming). From pre- to post-1: V(O2)max increased both in HL (+ 7.8%, P < 0.01) and in LL (+ 3.3%, P < 0.05), peak power output (PPO) tended to increase more (P=0.06) in HL (+ 4.1%, P < 0.01) than in LL (+ 1.9%). At post-15, V(O2)max has returned to pre-values in both groups, PPO increased more (P < 0.05) in HL (+ 8.3%, P < 0.01) than in LL (+ 3.8%), V(O2) and power at respiratory compensation point (RCP) increased more (P < 0.05) in HL (+ 9.5%, P < 0.01 and + 11.2%, P < 0.01) than in LL (+ 3.2 and + 3.3%). Cycling mechanical efficiency (8-5%) and economy during specific locomotion (7-7%) increased (P < 0.05) in both groups. This study shows that, for a similar increase in V(O2)max HL had a greater increase in PPO than LL. The efficiency of Hi-Lo is also evidenced 15 days later by higher V(O2) and power at RCP. This study emphasizes that during the post-altitude period, economy of work greatly increases in both groups.

The \"living high-training low\" model (Hi-Lo) may improve aerobic performance in athletes, and the main mechanism of this improvement is thought to be augmented erythropoiesis. A positive effect of Hi-Lo has been demonstrated previously by using altitudes of 2,000-3,000 m. Since the rate of erythropoiesis is altitude-dependent, we tested whether a higher altitude (3,500 m) during Hi-Lo increases erythropoiesis and maximal aerobic performance. Nordic skiers trained for 18 days at 1,200 m, while sleeping at 1,200 m in ambient air (control group, n = 5) or in hypoxic rooms (Hi-Lo, n = 6; 3 x 6 days at simulated altitudes of 2,500, 3,000 and finally 3,500 m, 11 h day(-1)). Measurements were done before, during (blood samples only) and 2 weeks after the intervention (POST). Maximal aerobic performance was examined from VO(2max) and time to exhaustion (T(exh)) at vVO(2max) (minimum speed associated with VO(2max)), respectively. Erythropoietin and soluble transferrin receptor responses were higher during Hi-Lo, whereas reticulocytes did not change. In POST (vs. before): hematological parameters were similar to basal levels, as well as red blood cell volume, being 2.68 +/- 0.83 l (vs. 2.64+/-0.54 l) in Hi-Lo and 2.62+/-0.57 l (vs. 2.87 +/- 0.59 l) in controls. At that time, neither VO(2max) nor T(exh) were improved by Hi-Lo, VO(2max) being non-significantly decreased by 2.0% (controls) and 3.7% (Hi-Lo). The present results suggest that increasing the altitude up to 3,500 m during Hi-Lo stimulates erythropoiesis but does not confer any advantage for maximal O2 transport.

The aim of this study was to determine the response of blood markers to acute hypoxia in high-level endurance athletes before training based on “living high-training low” model. Thirty endurance athletes performed a hypoxic cycling test and spent 3 h at rest in a simulated altitude of 3,000 m. At the end of the hypoxic cycling test, the quantity of the natural antisense transcript of HIF-1α mRNA (aHIF) transcript increased significantly (+37%, P  = 0.024). After 3-h exposure, at a simulated altitude of 3,000 m, the amount of HIF-1α mRNA increased significantly (+57%, P  = 0.012). Moreover, a large inter-subject range was observed in response to the hypoxic cycling test and to the prolonged hypoxic exposure: −133%/+79% and −82%/+653% for HIF-1α mRNA, 69%/+324% and −76%/+229% for aHIF. This study shows a large inter-variability of blood markers in elite athletes in response to acute hypoxic exposure corroborating previous observations made in other populations.

The \"living high-training low\" (LHTL) model is frequently used to enhance aerobic performance. However, the clinical tolerance and acclimatization process to this intermittent exposure needs to be examined. Forty one athletes from three federations (cross-country skiers, n=11; swimmers, n=18; runners, n=12) separately performed a 13 to 18-day training at the altitude of 1,200 m, by sleeping either at 1,200 m (CON) or in hypoxic rooms (HYP), with an O2 fraction corresponding to 2,500 m (5 nights for swimmers and 6 for skiers and runners), 3,000 m (6 nights for skiers, 8 for swimmers and 12 for runners) and 3,500 m (6 nights for skiers). Measurements performed before, 1 or 15 days after training were ventilatory response (HVRe) and desaturation (deltaSaO2e) during hypoxic exercise, an evaluation of cardiac function by echocardiography, and leukocyte count. Lake Louise AMS score and arterial O2 saturation during sleep were measured daily for HYP. Subjects did not develop symptoms of AMS. Mean nocturnal SaO2 decreased with altitude down to 90% at 3,500 m and increased with acclimatization (except at 3,500 m). Leukocyte count was not affected except at 3,500 m. The heart function was not affected by LHTL. Signs of ventilatory acclimatization were present immediately after training (increased HVRe and decreased deltaSaO2e) and had disappeared 15 days later. In conclusion, LHTL was well tolerated and compatible with aerobic training. Comparison of the three patterns of training suggests that a LHTL session should not exceed 3,000 m, for at least 18 days, with a minimum of 12 h day(-1) of exposure.

The \"living high-training low\" model (LHTL), i.e., training in normoxia but sleeping/living in hypoxia, is designed to improve the athletes performance. However, LHTL efficacy still remains controversial and also little is known about the duration of its potential benefit. This study tested whether LHTL enhances aerobic performance in athletes, and if any positive effect may last for up to 2 weeks after LHTL intervention. Eighteen swimmers trained for 13 days at 1,200 m while sleeping/living at 1,200 m in ambient air (control, n=9) or in hypoxic rooms (LHTL, n=9, 5 days at simulated altitude of 2,500 m followed by 8 days at simulated altitude of 3,000 m, 16 h day(-1)). Measures were done before 1-2 days (POST-1) and 2 weeks after intervention (POST-15). Aerobic performance was assessed from two swimming trials, exploring .VO(2max) and endurance performance (2,000-m time trial), respectively. Reticulocyte, serum EPO and soluble transferrin receptor responses were not altered by LHTL, whereas reticulocytes decreased in controls. In POST-1 (vs. before): red blood cell volume increased in LHTL only (+8.5%, P=0.03), .VO(2max) tended to increase more in LHTL (+8.1%, P=0.09) than in controls (+2.5%, P=0.21) without any difference between groups (P=0.42) and 2,000-m performance was unchanged with LHTL. In POST-15, both performance and hematological parameters were similar to initial levels. Our results indicate that LHTL may stimulate red cell production, without any concurrent amelioration of aerobic performance. The absence of any prolonged benefit after LHTL suggests that this LHTL model cannot be recommended for long-term purposes.