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

Contrary to our hypothesis that muscle iron proteins and myoglobin would 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, transferrin receptor, and total iron content

Paul Robach

2007

Scholarcy highlights

  • HA up-regulates iron acquisition by erythroid cells, mobilizes body iron, and increases hemoglobin concentration
  • The findings of the present study show that, in humans, this essential adaptive response to the early phase of hypoxia is associated with a net loss in the iron content of skeletal muscle, as indicated by the down-regulation of the iron proteins ferritin and transferrin receptor, and the possible up-regulation of ferroportin in muscle
  • By examining humans exposed to 7 to 9 days of severe hypoxia, the present study provides new insight into the molecular aspects of iron-oxygen interactions in response to altered systemic iron metabolism secondary to hypoxia-induced erythropoiesis
  • Our results strongly suggest that muscle tissue loses iron at high altitude: there is a decrease in L-ferritin, total iron, and TfR levels, an increase in ferroportin mRNA, and a decrease in myoglobin content
  • Regarding the molecular mechanism(s) associated with decreased muscle iron content, our tissue analyses revealed an unexpected response at high altitude, which conflicts with the classic iron regulatory elements/IRPmediated posttranscriptional regulation that usually leads to the coordinate but inverse expression of the 2 proteins
  • Whatever the mechanism may be, when considering the role of ferroportin in iron export and TfR in iron uptake, higher ferroportin mRNA levels and lower TfR expression are consistent with the loss of iron from the muscle cells of subjects exposed to high altitude
  • The connection between iron homeostasis and oxygen metabolism has been previously highlighted by molecular and cellular studies showing the role of iron in the modulation of hypoxia-inducible factor 1 activity and, the role of oxygen levels in regulating iron regulatory proteins activities. iron homeostasis is disrupted when HIF-1 is absent or up-regulated. The findings of the present study provide new insights into the interactions between iron distribution and oxygen homeostasis at the whole-body level in humans by suggesting that there is a net loss of iron from skeletal muscle during the systemic iron redistribution associated with high bone marrow iron uptake following hypoxia-enhanced erythropoiesis

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