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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.
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HEMATOPOIESIS
Strong iron demand during hypoxia-induced erythropoiesis is associated with down-regulation of iron-related proteins and myoglobin in human skeletal muscle
Paul Robach1,9,
Gaetano Cairo2,
Cecilia Gelfi3,
Francesca Bernuzzi2,
Henriette Pilegaard4,
Agnese Viganò3,
Paolo Santambrogio5,
Paolo Cerretelli3,
José A. L. Calbet6,
Stéphane Moutereau7, and
Carsten Lundby4,8
1 Département médical, Ecole Nationale de Ski et d'Alpinisme, Chamonix, France;
2 Institute of General Pathology, University of Milano, Italy;
3 Department of Sciences and Biomedical Technologies, University of Milano, Segrate, Italy;
4 The Copenhagen Muscle Research Centre and Centre of Inflammation and Metabolism, Institute of Molecular Biology and Physiology, University of Copenhagen, Denmark;
5 Protein Engineering Unit, Dibit, Instituto di Ricerca e Cura a Carattere Scientifico (IRCCS) H.S. Raffaele, Milano, Italy;
6 Department of Physical Education, University of Las Palmas de Gran Canaria, Spain;
7 Laboratoire de Biochimie, Hôpital Henri-Mondor, Créteil, France;
8 Department of Sport Science, University of Århus, Denmark;
9 Laboratoire "Réponses Cellulaires et Fonctionnelles à l'Hypoxie," Association pour la Recherche en Physiologie de l'Environment (ARPE), Université Paris 13, Bobigny, France
Iron is essential for oxygen transport because it is incorporated in the heme of the oxygen-binding proteins hemoglobin and myoglobin. An interaction between iron homeostasis and oxygen regulation is further suggested during hypoxia, in which 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 to 9 days of high altitude hypoxia (HA). 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 hypoxia-inducible factor 1 (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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