Sphingosine-1-phosphate (S1P) is a bioactive signalling lipid highly enriched in mature erythrocytes, with unknown functions pertaining to erythrocyte physiology. Here by employing nonbiased high-throughput metabolomic profiling, we show that erythrocyte S1P levels rapidly increase in 21 healthy lowland volunteers at 5,260 m altitude on day 1 and continue increasing to 16 days with concurrently elevated erythrocyte sphingonisne kinase 1 (Sphk1) activity and haemoglobin (Hb) oxygen (O₂) release capacity. Mouse genetic studies show that elevated erythrocyte Sphk1-induced S1P protects against tissue hypoxia by inducing O₂release. Mechanistically, we show that intracellular S1P promotes deoxygenated Hb anchoring to the membrane, enhances the release of membrane-bound glycolytic enzymes to the cytosol, induces glycolysis and thus the production of 2,3-bisphosphoglycerate (2,3-BPG), an erythrocyte-specific glycolytic intermediate, which facilitates O₂release. Altogether, we reveal S1P as an intracellular hypoxia-responsive biolipid promoting erythrocyte glycolysis, O₂delivery and thus new therapeutic opportunities to counteract tissue hypoxia.

We hypothesized that increasing exercise intensity recruits dormant arteriovenous intrapulmonary shunts, which may contribute to the widened alveolar-arterial oxygen difference seen with exercise. Twenty-three healthy volunteers (13 men and 10 women, aged 23–48 yr) with normal lung function and a wide range of fitness (mean maximal oxygen uptake = 126% predicted; range = 78–200% predicted) were studied by agitated saline contrast echocardiography (4-chamber apical view). All 23 subjects had normal resting contrast echocardiograms without evidence of intracardiac or intrapulmonary shunting. However, with cycle ergometer exercise, 21 of 23 (91%) of the subjects showed a delayed (>3 cardiac cycles) appearance of contrast bubbles in the left heart. This pattern is consistent with passage of contrast bubbles through the pulmonary circulation. Because the contrast bubbles are known to be significantly larger than pulmonary capillaries, we propose that they are traveling through direct arteriovenous intrapulmonary shunts. In all cases, the intrapulmonary shunting developed at submaximal oxygen uptakes [%maximal oxygen uptake = 59 ± 20 (SD)] and once evident persisted at all subsequent work rates. Within 3 min of exercise termination, the contrast echocardiograms with bubble injection showed no evidence of intrapulmonary shunting. These dynamic shunts will contribute significantly to the widened alveolar-arterial oxygen difference seen with exercise. They may also act as a protective parallel vascular network limiting the rise in regional pulmonary vascular pressure while preserving cardiac output during exercise.

It was not until 1984 that women were permitted to compete in the Olympic marathon. Today, more women than men participate in road racing in all distances except the marathon where participation is near equal. From the period of 1985 to 2004, the women’s marathon record improved at a rate three times greater than men’s. This has led many to question whether women are capable of surpassing men despite the fact that there remains a 10–12% performance gap in all distance events. The progressive developments in sports performance research and training, beginning with A.V. Hill’s establishment of the concept of VO_2max, have allowed endurance athletes to continue performance feats previously thought to be impossible. However, even today women are significantly underrepresented in sports performance research. By focusing more research on the female physiology and sex differences between men and women, we can better define how women differ from men in adapting to training and potentially use this information to improve endurance-exercise performance in women. The male advantage in endurance-exercise performance has commonly been attributed to their higher VO_2max, even when expressed as mL/kg/min. It is widely known that oxygen delivery is the primary limiting factor in elite athletes when it comes to improving VO_2max, but little research has explored the sex differences in oxygen delivery. Thus, the purpose of this review is to highlight what is known about the sex differences in the physiological factors contributing to VO_2max, more specifically oxygen delivery, and the impacts on performance.

Background: High altitude is a challenging condition caused by insufficient oxygen supply. Inability to adjust to hypoxia may lead to pulmonary edema, stroke, cardiovascular dysfunction, and even death. Thus, understanding the molecular basis of adaptation to high altitude may reveal novel therapeutics to counteract the detrimental consequences of hypoxia.Methods: Using high-throughput, unbiased metabolomic profiling, we report that the metabolic pathway responsible for production of erythrocyte 2,3-bisphosphoglycerate (2,3-BPG), a negative allosteric regulator of hemoglobin-O₂binding affinity, was significantly induced in 21 healthy humans within 2 hours of arrival at 5260 m and further increased after 16 days at 5260 m.Results: This finding led us to discover that plasma adenosine concentrations and soluble CD73 activity rapidly increased at high altitude and were associated with elevated erythrocyte 2,3-BPG levels and O₂releasing capacity. Mouse genetic studies demonstrated that elevated CD73 contributed to hypoxia-induced adenosine accumulation and that elevated adenosine-mediated erythrocyte A2B adenosine receptor activation was beneficial by inducing 2,3-BPG production and triggering O₂release to prevent multiple tissue hypoxia, inflammation, and pulmonary vascular leakage. Mechanistically, we demonstrated that erythrocyte AMP-activated protein kinase was activated in humans at high altitude and that AMP-activated protein kinase is a key protein functioning downstream of the A2B adenosine receptor, phosphorylating and activating BPG mutase and thus inducing 2,3-BPG production and O₂release from erythrocytes. Significantly, preclinical studies demonstrated that activation of AMP-activated protein kinase enhanced BPG mutase activation, 2,3-BPG production, and O₂release capacity in CD73-deficient mice, in erythrocyte-specific A2B adenosine receptor knockouts, and in wild-type mice and in turn reduced tissue hypoxia and inflammation.Conclusions: Together, human and mouse studies reveal novel mechanisms of hypoxia adaptation and potential therapeutic approaches for counteracting hypoxia-induced tissue damage.