Metabolic responses to hypoxia play important roles in cell survival strategies and disease pathogenesis in humans. However, the homeostatic adjustments that balance changes in energy supply and demand to maintain organismal function under chronic low oxygen conditions remain incompletely understood, making it difficult to distinguish adaptive from maladaptive responses in hypoxia-related pathologies. We integrated metabolomic and proteomic profiling with mitochondrial respirometry and blood gas analyses to comprehensively define the physiological responses of skeletal muscle energy metabolism to 16 days of high-altitude hypoxia (5260 m) in healthy volunteers from the AltitudeOmics project. In contrast to the view that hypoxia down-regulates aerobic metabolism, results show that mitochondria play a central role in muscle hypoxia adaptation by supporting higher resting phosphorylation potential and enhancing the efficiency of long-chain acylcarnitine oxidation. This directs increases in muscle glucose toward pentose phosphate and one-carbon metabolism pathways that support cytosolic redox balance and help mitigate the effects of increased protein and purine nucleotide catabolism in hypoxia. Muscle accumulation of free amino acids favor these adjustments by coordinating cytosolic and mitochondrial pathways to rid the cell of excess nitrogen, but might ultimately limit muscle oxidative capacity Collectively, these studies illustrate how an integration of aerobic and anaerobic metabolism is required for physiological hypoxia adaptation in skeletal muscle, and highlight protein catabolism and allosteric regulation as unexpected orchestrators of metabolic remodeling in this context. These findings have important implications for the management of hypoxia-related diseases and other conditions associated with chronic catabolic stress.

Introduction: Baroreflex sensitivity (BRS) is essential to ensure rapid adjustment to variations in blood pressure (BP). Little is known concerning the adaptive responses of BRS during acclimatization to high altitude at rest and during exercise.Methods: Twenty-one healthy sea-level residents were tested near sea level (SL, 130 m), the 1st (ALT1) and 16th day (ALT16) at 5,260 m using radial artery catheterization. BRS was calculated using the sequence method (direct interpretation of causal link between BP and heartrate). At rest, subjects breathed a hyperoxic mixture (250 mmHg O2, end tidal) to isolate the preponderance of CO2 chemoreceptors. End-tidal CO2 varied from 20 to 50 mmHg to assess peripheral chemoreflex. Rebreathing provoked incremental increase in CO2, increasing BP to assess baroreflex. During incremental cycling exercise to exhaustion, subjects breathed room air.Results: Resting BRS decreased in ALT1 which was exacerbated in ALT16. This decrease in ALT1 was reversible upon additional inspired CO2, but not in ALT16. BRS decrease during exercise was greater and occurred at lower workloads in ALT1 compared to SL. At ALT16, this decrease returned toward SL values.Discussion/Conclusion: This study is the first to report attenuated BRS in acute hypoxia, exacerbated in chronic hypoxia. In ALT1, hypocapnia triggered BRS reduction whilst in ALT16 resetting of chemoreceptor triggered BRS reduction. The exercise BRS resetting was impaired in ALT1 but normalized in ALT16. These BRS decreases indicate decreased control of BP and may explain deteriorations of cardiovascular status during exposure to high altitude.

Adult survivors of very preterm birth (PRET) have significantly lower aerobic exercise capacities than their counterparts born at term (CONT), but the underlying cause is unknown. To test whether expiratory flow limitation (EFL) during exercise negatively affects exercise endurance in PRET, we had PRET and CONT exercise to exhaustion breathing air and again breathing heliox. In PRET, EFL decreased and time-to-exhaustion increased significantly while breathing heliox. Heliox had a minimal effect on EFL and had no effect on time-to-exhaustion in CONT. We conclude that aerobic exercise endurance in PRET is limited, in part, by mechanical ventilatory constraints, specifically EFL.

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During exercise or while breathing hypoxic gas mixtures large diameter intrapulmonary arteriovenous anastomoses (IPAVA) open and can be detected with saline contrast echocardiography (SCE). The mechanisms regulating these vessels remain unknown, but both of these conditions activate the sympathetic nervous system and increase plasma catecholamine concentrations. We hypothesized that exogenously increasing the plasma epinephrine concentration would open IPAVA. Using SCE, we studied 5 subjects at rest, before and after continuous infusions of epinephrine at 20, 40, 80, 160, and 320 ng/kg/min for 3 min each. Cardiac output (Q) and pulmonary artery systolic pressure (PASP) were measured using ultrasound. Bubble scores (0–5) increased in a dose‐dependent fashion in all subjects to a max score ranging from 2–4. Q and PASP doubled at the highest infusion rate. After a 30 min break, epinephrine infusions were repeated while subjects breathed 100% O2 and bubble scores did not increase despite similar increases in cardiac output and PASP. These data demonstrate that during exercise or when breathing hypoxic gas mixtures the sympathetically‐mediated release of epinephrine may directly open IPAVA independent of changes in cardiac output or PASP. Mechanisms responsible for hyperoxia‐mediated closure remain elusive.Support: Eugene Evonuk Graduate Fellowship in Exercise & Environmental Physiology