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

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.

[1]  G. Cairo,et al.  A precious metal: Iron, an essential nutrient for all cells , 2006, Genes & Nutrition.

[2]  G. Musci,et al.  Ferroportin‐mediated mobilization of ferritin iron precedes ferritin degradation by the proteasome , 2006, The EMBO journal.

[3]  M. Gassmann,et al.  Excessive erythrocytosis in adult mice overexpressing erythropoietin leads to hepatic, renal, neuronal, and muscular degeneration. , 2006, American journal of physiology. Regulatory, integrative and comparative physiology.

[4]  G. Semenza,et al.  Hypoxia-inducible Factor-1 Deficiency Results in Dysregulated Erythropoiesis Signaling and Iron Homeostasis in Mouse Development* , 2006, Journal of Biological Chemistry.

[5]  B. Saltin,et al.  Effects of ATP-induced leg vasodilation on VO2 peak and leg O2 extraction during maximal exercise in humans. , 2006, American journal of physiology. Regulatory, integrative and comparative physiology.

[6]  T. Ganz,et al.  Regulation of iron acquisition and iron distribution in mammals. , 2006, Biochimica et biophysica acta.

[7]  P. Cerretelli,et al.  The human muscle proteome in aging. , 2006, Journal of proteome research.

[8]  A. Donovan,et al.  The ins and outs of iron homeostasis. , 2006, Physiology.

[9]  Daryl R. Williams,et al.  Hypoxia-inducible myoglobin expression in nonmuscle tissues. , 2006, Proceedings of the National Academy of Sciences of the United States of America.

[10]  T. Ganz,et al.  Iron imports. IV. Hepcidin and regulation of body iron metabolism. , 2006, American journal of physiology. Gastrointestinal and liver physiology.

[11]  D. Conte,et al.  Iron regulatory proteins 1 and 2 in human monocytes, macrophages and duodenum: expression and regulation in hereditary hemochromatosis and iron deficiency. , 2006, Haematologica.

[12]  P. Neufer,et al.  Gene expression in human skeletal muscle: alternative normalization method and effect of repeated biopsies , 2005, European Journal of Applied Physiology.

[13]  G. Cairo,et al.  Loss of the von Hippel Lindau Tumor Suppressor Disrupts Iron Homeostasis in Renal Carcinoma Cells* , 2005, Journal of Biological Chemistry.

[14]  Jerry Kaplan,et al.  Hepcidin Regulates Cellular Iron Efflux by Binding to Ferroportin and Inducing Its Internalization , 2004, Science.

[15]  Daniel J Garry,et al.  Myoglobin: an essential hemoprotein in striated muscle , 2004, Journal of Experimental Biology.

[16]  P. Arosio,et al.  Analysis of the biologic functions of H- and L-ferritins in HeLa cells by transfection with siRNAs and cDNAs: evidence for a proliferative role of L-ferritin. , 2004, Blood.

[17]  P. Cerretelli,et al.  The FASEB Journal express article 10.1096/fj.03-1077fje. Published online January 20, 2004. New aspects of altitude adaptation in Tibetans: a proteomic approach , 2022 .

[18]  K. Iwai,et al.  Genetic ablations of iron regulatory proteins 1 and 2 reveal why iron regulatory protein 2 dominates iron homeostasis , 2004, The EMBO journal.

[19]  K. Westerterp,et al.  Comparative response of EPO and soluble transferrin receptor at high altitude. , 2004, Medicine and science in sports and exercise.

[20]  Marie-Pierre Dubé,et al.  Mutations in HFE2 cause iron overload in chromosome 1q–linked juvenile hemochromatosis , 2004, Nature Genetics.

[21]  B. Wittenberg,et al.  Myoglobin function reassessed , 2003, Journal of Experimental Biology.

[22]  Henriette Pilegaard,et al.  Exercise induces transient transcriptional activation of the PGC‐1α gene in human skeletal muscle , 2003, The Journal of physiology.

[23]  Gaël Nicolas,et al.  The gene encoding the iron regulatory peptide hepcidin is regulated by anemia, hypoxia, and inflammation. , 2002, The Journal of clinical investigation.

[24]  K. Pantopoulos,et al.  Conditional Derepression of Ferritin Synthesis in Cells Expressing a Constitutive IRP1 Mutant , 2002, Molecular and Cellular Biology.

[25]  H. Hoppeler,et al.  Muscle tissue adaptations to hypoxia. , 2001, The Journal of experimental biology.

[26]  U. Flögel,et al.  Myoglobin: A scavenger of bioactive NO. , 2001, Proceedings of the National Academy of Sciences of the United States of America.

[27]  G. Cairo,et al.  Iron regulatory proteins in pathobiology. , 2000, The Biochemical journal.

[28]  P. Neufer,et al.  Transcriptional regulation of gene expression in human skeletal muscle during recovery from exercise. , 2000, American journal of physiology. Endocrinology and metabolism.

[29]  S. Abboud,et al.  A Novel Mammalian Iron-regulated Protein Involved in Intracellular Iron Metabolism* , 2000, The Journal of Biological Chemistry.

[30]  G. Semenza.  HIF-1: mediator of physiological and pathophysiological responses to hypoxia. , 2000, Journal of applied physiology.

[31]  R J Simpson,et al.  A novel duodenal iron-regulated transporter, IREG1, implicated in the basolateral transfer of iron to the circulation. , 2000, Molecular cell.

[32]  L. Bianchi,et al.  HIF-1-mediated activation of transferrin receptor gene transcription by iron chelation. , 1999, Nucleic acids research.

[33]  L. Bianchi,et al.  Transferrin Receptor Induction by Hypoxia , 1999, The Journal of Biological Chemistry.

[34]  C. Lok,et al.  Identification of a Hypoxia Response Element in the Transferrin Receptor Gene* , 1999, The Journal of Biological Chemistry.

[35]  G. Cairo,et al.  Lack of coordinate control of ferritin and transferrin receptor expression during rat liver regeneration , 1998, Hepatology.

[36]  M. Hentze,et al.  Molecular control of vertebrate iron metabolism: mRNA-based regulatory circuits operated by iron, nitric oxide, and oxidative stress. , 1996, Proceedings of the National Academy of Sciences of the United States of America.

[37]  J. Leigh,et al.  Myoglobin O2 desaturation during exercise. Evidence of limited O2 transport. , 1995, The Journal of clinical investigation.

[38]  A. Tomasi,et al.  Induction of Ferritin Synthesis by Oxidative Stress , 1995, The Journal of Biological Chemistry.

[39]  A. Albertini,et al.  The role of the L-chain in ferritin iron incorporation. Studies of homo and heteropolymers. , 1994, Journal of molecular biology.

[40]  J. Richalet,et al.  Control of erythropoiesis in humans during prolonged exposure to the altitude of 6,542 m. , 1994, The American journal of physiology.

[41]  L. Kühn,et al.  Interleukin-2-dependent transcriptional and post-transcriptional regulation of transferrin receptor mRNA. , 1993, The Journal of biological chemistry.

[42]  Y. Beguin.  The soluble transferrin receptor: biological aspects and clinical usefulness as quantitative measure of erythropoiesis. , 1992, Haematologica.

[43]  G. Cairo,et al.  Regulation of hepatic transferrin, transferrin receptor and ferritin genes in human siderosis , 1991, Hepatology.

[44]  C. Sylvén,et al.  Is hypoxia a stimulus for synthesis of oxidative enzymes and myoglobin? , 1990, Journal of applied physiology.

[45]  Barbara Neupert,et al.  A specific mRNA binding factor regulates the iron-dependent stability of cytoplasmic transferrin receptor mRNA , 1989, Cell.

[46]  P. Chomczyński,et al.  Single-step method of RNA isolation by acid guanidinium thiocyanate-phenol-chloroform extraction. , 1987, Analytical biochemistry.

[47]  Boulton Fe.  The myoglobin content of human skeletal muscle. , 1973 .

[48]  F. Boulton.  The myoglobin content of human skeletal muscle. , 1973, British Journal of Haematology.

[49]  L. Pugh.  Blood volume and haemoglobin concentration at altitudes above 18,000 ft. (5500 m) , 1964, The Journal of physiology.

[50]  B. Reynafarje.  Myoglobin content and enzymatic activity of muscle and altitude adaptation. , 1962, Journal of applied physiology.

[51]  C. Reynafarje,et al.  The polycythemia of high altitudes: iron metabolism and related aspects. , 1959, Blood.

[52]  B. E. Vaughan,et al.  Changes in myoglobin content of the high altitude acclimatized rat. , 1956, The American journal of physiology.