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Blood, 1 June 2007, Vol. 109, No. 11, pp. 4724-4731. Prepublished online as a Blood First Edition Paper on February 20, 2007; DOI 10.1182/blood-2006-08-040006.
Submitted August 7, 2006
Departement medical, Ecole Nationale de Ski et d'Alpinisme, Chamonix, France * Corresponding author; email: gaetano.cairo{at}unimi.it.
Iron is essential for oxygen transport because it is incorporated in the heme of oxygen-binding proteins hemoglobin and myoglobin. An interaction between iron homeostasis and oxygen regulation is further suggested during hypoxia, where hemoglobin and myoglobin syntheses have been reported to increase. This study gives new insights into the changes in iron content and iron-oxygen interactions during enhanced erythropoiesis by simultaneously analyzing blood and muscle samples in humans exposed to 7-9 days of high altitude (HA) hypoxia. HA up-regulates iron acquisition by erythroid cells, mobilizes body iron and increases hemoglobin concentration. However, contrary to our hypothesis that muscle iron proteins and myoglobin would also be up-regulated during HA, this study shows that HA lowers myoglobin expression by 35% and down-regulates iron-related proteins in skeletal muscle, as evidenced by decreases in L-ferritin (43%), transferrin receptor (TfR) (50%), and total iron content (37%). This parallel decrease in L-ferritin and TfR in HA occurs independently of increased HIF-1 mRNA levels and unchanged binding activity of iron regulatory proteins, but concurrently with increased ferroportin mRNA levels, suggesting enhanced iron export. Thus, in HA, the elevated iron requirement associated with enhanced erythropoiesis presumably elicits iron mobilization and myoglobin down-modulation, suggesting an altered muscle oxygen homeostasis.
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