Strong iron demand during hypoxia-induced erythropoiesis is associated with down-regulation of iron-related proteins and myoglobin in human skeletal muscle

Abstract

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.

Cell-specific regulation of Ferroportin transcription following experimentally-induced acute anemia in mice

“…Inflammatory stimuli, such as LPS [12], TNFα [24] and turpentine oil [15] can also regulate FPN mRNA levels, both in vivo and in vitro. In addition, it has been reported that high-altitude exposure is associated with an increase in skeletal muscle FPN mRNA levels in humans [14].…”

Iron deficiency in pulmonary arterial hypertension: a potential therapeutic target

“…Myoglobin scavenges nitric oxide and reactive oxygen species under oxygenated conditions and produces nitric oxide from nitrite under deoxygenated conditions [34,35]. Studies in human volunteers indicate that in some situations where erythropoiesis is strongly stimulated, for example at high altitude (4,500 m), myoglobin may represent a source of iron for haemoglobin production [36]. This effect contrasts with previously noted adaptations to chronic hypoxia; increased skeletal muscle myoglobin has been demonstrated in humans and animals living at high altitude and deep-sea diving animals [37][38][39].…”

Inadequate Myocardial Oxygen Supply/Demand in Experimental Pulmonary Hypertension

“…It may be that the capacity to synthesize myoglobin (e.g. the increased cytoplasm/nucleus ratio or the www.intechopen.com availability of iron (Rohbach et al, 2007) is the limiting factor, or that degradation of myoglobin in hypertrophied cardiomyocytes is increased, e.g. due to H 2 O 2 production.…”