The regulation of human iron metabolism in hypoxia

Abstract

Athletes commonly use altitude exposure in an attempt to improve their aerobic performance at sea level. Altitude exposure enhances erythropoiesis and iron-dependent oxidative and glycolytic enzyme production, for this reason, athletes must maintain a healthy iron balance at altitude. A negative iron balance at altitude may limit such physiological adaptations, potentially reducing the performance benefits of altitude exposure. This thesis examined the regulation of iron metabolism during acute (~31 min, Study One) and prolonged altitude exposure (14 days, Study Two). Finally, Study Three examined how daily oral iron supplementation influenced haemoglobin mass (Hbmass) and iron parameter responses to prolonged, moderate altitude exposure in a large cohort of elite athletes. Specifically, Study One found acute (~31 min) interval exercise [5 × 4 min at 90% of the maximal aerobic running velocity (vVO2max)] increased post-exercise interleukin-6 (IL-6) production and elevated hepcidin production 3 h thereafter in both normoxia (fraction of inspired oxygen (FIO2) = 0.2093) and normobaric hypoxia (i.e. 3,000 m simulated altitude; FIO2 = 0.1450). These results suggest exercise performed in acute hypoxia does not alter the post-exercise hepcidin response, relative to exercise in normoxia, possibly owing to the short duration of the hypoxic stimulus. Prolonged altitude exposure suppresses resting hepcidin levels in sojourning mountaineers, but its influence on the post-exercise hepcidin response exercise has not yet been investigated. Therefore, Study Two investigated how 14 days of live high: train low (LHTL) (exposure to 3,000 m simulated altitude for 14 h.d-1) influenced resting levels of hepcidin, erythropoietin (EPO) and blood iron parameters. Study Two also examined the post-exercise hepcidin and iron parameter responses to interval exercise (5 × 1,000 m at 90% of the maximal aerobic running velocity) performed in normoxia (600 m natural altitude) and normobaric hypoxia (i.e. ~3,000 m simulated altitude), following 11 and 14 days of LHTL. The post-exercise hepcidin response was compared with interval exercise performed at a matched exercise intensity in normoxia or hypoxia before LHTL. Here, LHTL suppressed resting hepcidin levels after two days of exposure, but the post-exercise hepcidin response to interval exercise was similar in normoxia and hypoxia, both before and after LHTL. Additionally, Hbmass increased by 2.2% and plasma ferritin levels decreased following LHTL. In conclusion, prolonged, moderate altitude exposure suppresses resting hepcidin levels, which likely ensures more iron can be transported to the erythron to support accelerated erythropoiesis. Prolonged altitude exposure places a large burden on body iron stores because additional iron is required to support accelerated erythropoiesis. Accordingly, athletes often ingest oral iron supplements during altitude exposure to ensure they maintain a healthy iron balance. By analysing ten years of haematological data collected from welltrained athletes who undertook two-to-four weeks of LHTL at simulated (3,000 m) or natural (1,350-2,700 m) altitudes, Study Three established how oral iron supplement dose moderates the Hbmass, serum ferritin and transferrin saturation response to prolonged moderate altitude exposure. In general, athletes supplemented with 105 mg.d- 1 or 210 mg.d-1 of oral iron supplement increased their Hbmass from pre-altitude levels by 3.3% and 4.0% respectively. Serum ferritin levels decreased by 33.2% in non-iron supplemented athletes and by 13.8% in athletes supplemented with 105 mg.d-1 of oral iron, however, those athletes who ingested 210 mg.d-1 markedly increased their iron storage compartment by 36.8% after moderate altitude exposure. Thus, daily oral iron supplementation at altitude assists athletes to maintain a healthy iron balance, providing them with sufficient iron to sustain accelerated erythropoiesis. In conclusion, this thesis suggests exercise in acute hypoxia does not seem to alter the post-exercise hepcidin response relative to exercise in normoxia, but prolonged altitude exposure suppresses resting hepcidin levels and may attenuate the magnitude of postexercise hepcidin response after 14 days of LHTL. Finally, daily oral iron supplementation may support iron balance and Hbmass production in athletes undertaking prolonged moderate altitude exposure