Iron Homeostasis in Elite Athletes and Ultramarathon Runners

AIM: The present study was aimed at determining the effect of two different types of exercise (elite athletes playing football and ultramarathon runners on iron metabolism and, especially, the role of hepcidin in iron homeostasis. MATERIAL & METHOD: Two groups of athletes were investigated. The first group consisted of 19 male elite football athletes and the second group of 41 ultramarathon runners. In both cases, blood samples were taken pre-race (t1), immediately post-race (t2), and 24 hours post-race for football athletes or 36-48 hours post-race for ultramarathon athletes (t3). RESULTS: The iron levels in time t3 were found to have statistically significant decreases compared with the iron levels in pre-race and post-race period. Moreover, ferritin levels increased significantly in times t2 and t3. Hepcidin levels increased in time t2 in football players (from 27.45 ± 12.98 to 37.42 ± 13.74 ng/mL) and decreased in time t3. However, in ultramarathon runners, hepcidin levels significantly increased in time t2 (from 29.16 ± 10.92 to 58.81 ± 16.97 ng/mL) and remained increased in time t3 (37.69 ± 16.38 ng/mL), despite a trend for decrease. In football players, sTfR levels did not change, contrary to ultramarathon runners, where sTfR levels were found decreased in times t2 and t3. CONCLUSIONS: Iron metabolism in athletes can be impacted by the type of exercise. Ferritin is not a reliable marker for iron balance because, in the present study, it is more likely an acute-phase protein. The main regulator of iron homeostasis, hepcidin, increased, showing the body’s response to inflammation, by trapping iron in the macrophages and by altering iron absorption. Finally, a strenuous and prolonged exercise can lead to sports anemia.

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Hepatic HIF-2 regulates erythropoietic responses to hypoxia in renal anemia

Blood ◽

10.1182/blood-2010-02-270322 ◽

2010 ◽

Vol 116 (16) ◽

pp. 3039-3048 ◽

Cited By ~ 175

Author(s):

Pinelopi P. Kapitsinou ◽

Qingdu Liu ◽

Travis L. Unger ◽

Jennifer Rha ◽

Olena Davidoff ◽

...

Keyword(s):

Iron Metabolism ◽

Iron Homeostasis ◽

Tissue Oxygenation ◽

Hypoxia Inducible Factor ◽

Gene Inactivation ◽

Renal Anemia ◽

Hypoxic Induction ◽

Main Regulator

Abstract The kidney is the main physiologic source of erythropoietin (EPO) in the adult and responds to decreases in tissue oxygenation with increased EPO production. Although studies in mice with liver-specific or global gene inactivation have shown that hypoxia-inducible factor 2 (Hif-2) plays a major role in the regulation of Epo during infancy and in the adult, respectively, the contribution of renal HIF-2 signaling to systemic EPO homeostasis and the role of extrarenal HIF-2 in erythropoiesis, in the absence of kidney EPO, have not been examined directly. Here, we used Cre-loxP recombination to ablate Hif-2α in the kidney, whereas Hif-2–mediated hypoxia responses in the liver and other Epo-producing tissues remained intact. We found that the hypoxic induction of renal Epo is completely Hif-2 dependent and that, in the absence of renal Hif-2, hepatic Hif-2 takes over as the main regulator of serum Epo levels. Furthermore, we provide evidence that hepatocyte-derived Hif-2 is involved in the regulation of iron metabolism genes, supporting a role for HIF-2 in the coordination of EPO synthesis with iron homeostasis.

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Role of iron metabolism-regulator hepcidin in perinatal iron homeostasis

Orvosi Hetilap ◽

10.1556/oh.2010.28773 ◽

2010 ◽

Vol 151 (3) ◽

pp. 83-91 ◽

Cited By ~ 1

Author(s):

Ádám Balogh ◽

Szilvia Bősze ◽

Kata Horváti ◽

Gábor Mező ◽

Sándor Kéki ◽

...

Keyword(s):

Iron Metabolism ◽

Iron Homeostasis

A hepcidin egy nemrégiben felfedezett, defenzin típusú peptid, amely központi szerepet játszik a vasháztartás szabályozásában. A hepcidin csökkenti a vastranszportban szerepet játszó molekulák expresszióját, így gátolja a vas gastrointestinalis rendszerből való felszívódását, makrofágokból való felszabadulását, csökkentve ezzel a szérum vasszintjét. A hepcidin vasháztartásban betöltött szerepének tisztázása segíthet a gyulladásos és krónikus betegségekben bekövetkező anémia pontosabb megértésében. Munkánk kezdetén a hepcidin kimutatására alkalmas, kereskedelmi forgalomban elérhető módszer nem állt rendelkezésre. Célunk volt egy, a vizelethepcidin kimutatására alkalmas módszer kidolgozása, valamint hogy ezen módszer segítségével vizsgáljuk a hepcidin jelentőségét a perinatalis vasháztartásban. Munkánk során a natív, emberi hepcidin aminosav-szekvenciájának megfelelően állítottunk elő peptidszármazékokat, amelyek közül az 1-7 peptidszármazékról igazoltuk, hogy alkalmas lehet a natív hepcidin standard helyettesítésére immunreakción alapuló módszerek fejlesztésekor. Kidolgoztunk egy, az emberi vizelethepcidin mennyiségi meghatározására alkalmas, lézerdeszorpciós tömegspektrometriás, szemikvantitatív módszert, amelyben az általunk szintetizált acetil-1-25 peptidszármazékot mint hepcidinszerű belső standardot elsőként alkalmaztuk. Kidolgoztunk a vizelet tisztítására és a vizelethepcidin koncentrálására alkalmas, szilárd fázisú extrakción alapuló módszert. Az általunk kidolgozott módszerrel elsőként mértük egészséges újszülöttek vizelethepcidin-szintjét, valamint egy kereskedelmi forgalomban elérhető módszerrel a szérumprohepcidin-szintjét. Kimutattuk, hogy az érett újszülöttek korai adaptációja során a szérumprohepcidin-szint nem változik, a vizelethepcidin viszont szignifikánsan nő. A szérumprohepcidin- és a vizelethepcidin-szintek egymással nem mutattak összefüggést. Kimutattuk, hogy az érett újszülöttek vasháztartásának korai adaptációja során a szérumprohepcidin-szintek kizárólag a vörösvérsejtek átlagos hemoglobinkoncentrációjával, míg a vizelethepcidin-szintek a szérumvasszinttel és teljes vaskötő kapacitással mutattak összefüggést. Kimutattuk, hogy az érett újszülöttek vasháztartásának korai adaptációja során a köldökzsinórvér-mintákban az alacsonyabb szérumprohepcidin-szintek esetén szabad vas jelenléte igazolható. Összefoglalva: Eredményeink alapján elmondhatjuk, hogy a hepcidinnek valószínűleg szerepe van az újszülöttek korai, a vasháztartást érintő adaptációjában, azonban további vizsgálatok szükségesek ahhoz, hogy ezt az összefüggést biztosan megállapíthassuk.

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Normal systemic iron homeostasis in mice with macrophage-specific deletion of transferrin receptor 2

AJP Gastrointestinal and Liver Physiology ◽

10.1152/ajpgi.00291.2015 ◽

2016 ◽

Vol 310 (3) ◽

pp. G171-G180 ◽

Cited By ~ 10

Author(s):

Gautam Rishi ◽

Eriza S. Secondes ◽

Daniel F. Wallace ◽

V. Nathan Subramaniam

Keyword(s):

Iron Metabolism ◽

Knockout Mice ◽

Transferrin Receptor ◽

Iron Homeostasis ◽

Essential Element ◽

Cellular Growth ◽

Hepatic Expression ◽

Specific Deletion ◽

Transferrin Receptor 2

Iron is an essential element, since it is a component of many macromolecules involved in diverse physiological and cellular functions, including oxygen transport, cellular growth, and metabolism. Systemic iron homeostasis is predominantly regulated by the liver through the iron regulatory hormone hepcidin. Hepcidin expression is itself regulated by a number of proteins, including transferrin receptor 2 (TFR2). TFR2 has been shown to be expressed in the liver, bone marrow, macrophages, and peripheral blood mononuclear cells. Studies from our laboratory have shown that mice with a hepatocyte-specific deletion of Tfr2 recapitulate the hemochromatosis phenotype of the global Tfr2 knockout mice, suggesting that the hepatic expression of TFR2 is important in systemic iron homeostasis. It is unclear how TFR2 in macrophages contributes to the regulation of iron metabolism. We examined the role of TFR2 in macrophages by analysis of transgenic mice lacking Tfr2 in macrophages by crossing Tfr2 f/f mice with LysM-Cre mice. Mice were fed an iron-rich diet or injected with lipopolysaccharide to examine the role of macrophage Tfr2 in iron- or inflammation-mediated regulation of hepcidin. Body iron homeostasis was unaffected in the knockout mice, suggesting that macrophage TFR2 is not required for the regulation of systemic iron metabolism. However, peritoneal macrophages of knockout mice had significantly lower levels of ferroportin mRNA and protein, suggesting that TFR2 may be involved in regulating ferroportin levels in macrophages. These studies further elucidate the role of TFR2 in the regulation of iron homeostasis and its role in regulation of ferroportin and thus macrophage iron homeostasis.

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Role of Dietary Flavonoids in Iron Homeostasis

Pharmaceuticals ◽

10.3390/ph12030119 ◽

2019 ◽

Vol 12 (3) ◽

pp. 119 ◽

Cited By ~ 2

Author(s):

Marija Lesjak ◽

Surjit K. S. Srai

Keyword(s):

Iron Metabolism ◽

Iron Homeostasis ◽

Iron Absorption ◽

Therapeutic Potential ◽

State Of The Art ◽

Iron Status ◽

Dietary Factors ◽

The Body ◽

Dietary Flavonoids

Balancing systemic iron levels within narrow limits is critical for human health, as both iron deficiency and overload lead to serious disorders. There are no known physiologically controlled pathways to eliminate iron from the body and therefore iron homeostasis is maintained by modifying dietary iron absorption. Several dietary factors, such as flavonoids, are known to greatly affect iron absorption. Recent evidence suggests that flavonoids can affect iron status by regulating expression and activity of proteins involved the systemic regulation of iron metabolism and iron absorption. We provide an overview of the links between different dietary flavonoids and iron homeostasis together with the mechanism of flavonoids effect on iron metabolism. In addition, we also discuss the clinical relevance of state-of-the-art knowledge regarding therapeutic potential that flavonoids may have for conditions that are low in iron such as anaemia or iron overload diseases.

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Crucial function of vertebrate glutaredoxin 3 (PICOT) in iron homeostasis and hemoglobin maturation

Molecular Biology of the Cell ◽

10.1091/mbc.e12-09-0648 ◽

2013 ◽

Vol 24 (12) ◽

pp. 1895-1903 ◽

Cited By ~ 70

Author(s):

Petra Haunhorst ◽

Eva-Maria Hanschmann ◽

Lars Bräutigam ◽

Oliver Stehling ◽

Bastian Hoffmann ◽

...

Keyword(s):

Iron Metabolism ◽

Iron Homeostasis ◽

Regulatory Protein ◽

Iron Regulation ◽

Iron Starvation ◽

Intracellular Iron ◽

Cellular Iron ◽

Cellular Iron Uptake ◽

S Proteins

The mechanisms by which eukaryotic cells handle and distribute the essential micronutrient iron within the cytosol and other cellular compartments are only beginning to emerge. The yeast monothiol multidomain glutaredoxins (Grx) 3 and 4 are essential for both transcriptional iron regulation and intracellular iron distribution. Despite the fact that the mechanisms of iron metabolism differ drastically in fungi and higher eukaryotes, the glutaredoxins are conserved, yet their precise function in vertebrates has remained elusive. Here we demonstrate a crucial role of the vertebrate-specific monothiol multidomain Grx3 (PICOT) in cellular iron homeostasis. During zebrafish embryonic development, depletion of Grx3 severely impairs the maturation of hemoglobin, the major iron-consuming process. Silencing of human Grx3 expression in HeLa cells decreases the activities of several cytosolic Fe/S proteins, for example, iron-regulatory protein 1, a major component of posttranscriptional iron regulation. As a consequence, Grx3-depleted cells show decreased levels of ferritin and increased levels of transferrin receptor, features characteristic of cellular iron starvation. Apparently, Grx3-deficient cells are unable to efficiently use iron, despite unimpaired cellular iron uptake. These data suggest an evolutionarily conserved role of cytosolic monothiol multidomain glutaredoxins in cellular iron metabolism pathways, including the biogenesis of Fe/S proteins and hemoglobin maturation.

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Iron Metabolism in Obesity and Metabolic Syndrome

International Journal of Molecular Sciences ◽

10.3390/ijms21155529 ◽

2020 ◽

Vol 21 (15) ◽

pp. 5529

Author(s):

Álvaro González-Domínguez ◽

Francisco M. Visiedo-García ◽

Jesús Domínguez-Riscart ◽

Raúl González-Domínguez ◽

Rosa M. Mateos ◽

...

Keyword(s):

Childhood Obesity ◽

Iron Metabolism ◽

Fenton Reaction ◽

Iron Homeostasis ◽

Living Organism ◽

Nutritional Disorder ◽

Nonalcoholic Fatty Liver ◽

Pathological Conditions

Obesity is an excessive adipose tissue accumulation that may have detrimental effects on health. Particularly, childhood obesity has become one of the main public health problems in the 21st century, since its prevalence has widely increased in recent years. Childhood obesity is intimately related to the development of several comorbidities such as nonalcoholic fatty liver disease, dyslipidemia, type 2 diabetes mellitus, non-congenital cardiovascular disease, chronic inflammation and anemia, among others. Within this tangled interplay between these comorbidities and associated pathological conditions, obesity has been closely linked to important perturbations in iron metabolism. Iron is the second most abundant metal on Earth, but its bioavailability is hampered by its ability to form highly insoluble oxides, with iron deficiency being the most common nutritional disorder. Although every living organism requires iron, it may also cause toxic oxygen damage by generating oxygen free radicals through the Fenton reaction. Thus, iron homeostasis and metabolism must be tightly regulated in humans at every level (i.e., absorption, storage, transport, recycling). Dysregulation of any step involved in iron metabolism may lead to iron deficiencies and, eventually, to the anemic state related to obesity. In this review article, we summarize the existent evidence on the role of the most recently described components of iron metabolism and their alterations in obesity.

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Role of Fermented Goat Milk on Liver Gene and Protein Profiles Related to Iron Metabolism during Anemia Recovery

Nutrients ◽

10.3390/nu12051336 ◽

2020 ◽

Vol 12 (5) ◽

pp. 1336

Author(s):

Jorge Moreno-Fernandez ◽

María J. M. Alférez ◽

Inmaculada López-Aliaga ◽

Javier Díaz-Castro

Keyword(s):

Iron Deficiency ◽

Protein Expression ◽

Iron Metabolism ◽

Iron Homeostasis ◽

Goat Milk ◽

Milk Consumption ◽

Gene And Protein Expression ◽

Key Genes ◽

Liver Gene

Despite the crucial role of the liver as the central regulator of iron homeostasis, no studies have directly tested the modulation of liver gene and protein expression patterns during iron deficiency instauration and recovery with fermented milks. Fermented goat milk consumption improves the key proteins of intestinal iron metabolism during iron deficiency recovery, enhancing the digestive and metabolic utilization of iron. The aim of this study was to assess the influence of fermented goat or cow milk consumption on liver iron homeostasis during iron-deficiency anemia recovery with normal or iron-overload diets. Analysis included iron status biomarkers, gene and protein expression in hepatocytes. In general, fermented goat milk consumption either with normal or high iron content up-regulated liver DMT1, FPN1 and FTL1 gene expression and DMT1 and FPN1 protein expression. However, HAMP mRNA expression was lower in all groups of animals fed fermented goat milk. Additionally, hepcidin protein expression decreased in control and anemic animals fed fermented goat milk with normal iron content. In conclusion, fermented goat milk potentiates the up-regulation of key genes coding for proteins involved in iron metabolism, such as DMT1, and FPN1, FTL1 and down-regulation of HAMP, playing a key role in enhanced iron repletion during anemia recovery, inducing a physiological adaptation of the liver key genes and proteins coordinated with the fluctuation of the cellular iron levels, favoring whole-body iron homeostasis.

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Role of Iron Metabolism-Related Genes in Prenatal Development: Insights from Mouse Transgenic Models

Genes ◽

10.3390/genes12091382 ◽

2021 ◽

Vol 12 (9) ◽

pp. 1382

Author(s):

Zuzanna Kopeć ◽

Rafał R. Starzyński ◽

Aneta Jończy ◽

Rafał Mazgaj ◽

Paweł Lipiński

Keyword(s):

Iron Metabolism ◽

Iron Homeostasis ◽

Current Knowledge ◽

Prenatal Development ◽

Postnatal Life ◽

Mammalian Development ◽

Knock Out ◽

Stage Of Development ◽

Essential Nutrient

Iron is an essential nutrient during all stages of mammalian development. Studies carried out over the last 20 years have provided important insights into cellular and systemic iron metabolism in adult organisms and led to the deciphering of many molecular details of its regulation. However, our knowledge of iron handling in prenatal development has remained remarkably under-appreciated, even though it is critical for the health of both the embryo/fetus and its mother, and has a far-reaching impact in postnatal life. Prenatal development requires a continuous, albeit quantitatively matched with the stage of development, supply of iron to support rapid cell division during embryogenesis in order to meet iron needs for erythropoiesis and to build up hepatic iron stores, (which are the major source of this microelement for the neonate). Here, we provide a concise overview of current knowledge of the role of iron metabolism-related genes in the maintenance of iron homeostasis in pre- and post-implantation development based on studies on transgenic (mainly knock-out) mouse models. Most studies on mice with globally deleted genes do not conclude whether underlying in utero iron disorders or lethality is due to defective placental iron transport or iron misregulation in the embryo/fetus proper (or due to both). Therefore, there is a need of animal models with tissue specific targeted deletion of genes to advance the understanding of prenatal iron metabolism.

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The role of iron in pulmonary pathology

Multidisciplinary Respiratory Medicine ◽

10.4081/mrm.2015.337 ◽

2019 ◽

Vol 10 ◽

Author(s):

Heena Khiroya ◽

Alice M. Turner

Keyword(s):

Lung Cancer ◽

Pulmonary Disease ◽

Respiratory Disease ◽

Cigarette Smoke ◽

Iron Metabolism ◽

Iron Homeostasis ◽

Association Studies ◽

Regulatory Protein ◽

Chronic Obstructive

Respiratory disease accounts for a large proportion of emergency admissions to hospital and diseaseassociated mortality. Genetic association studies demonstrate a link between iron metabolism and pulmonary disease phenotypes. IREB2 is a gene that produces iron regulatory protein 2 (IRP2), which has a key role in iron homeostasis. This review addresses pathways involved in iron metabolism, particularly focusing on the role of IREB2 . In addition to this, environmental factors also influence phenotypic variation in respiratory disease, for example inhaled iron from cigarette smoke is deposited in the lung and causes tissue damage by altering iron homeostasis. The effects of cigarette smoke are detailed in this article, particularly in relation to lung conditions that favour the upper lobes, such as emphysema and lung cancer. Clinical applications of iron homeostasis are also discussed in this review, especially looking at the pathophysiology of chronic obstructive pulmonary disease, lung cancer, pulmonary infections and acute respiratory distress syndrome. Promising new treatments involving iron are also covered.

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Genome-resolved metagenomics reveals role of iron metabolism in drought-induced rhizosphere microbiome dynamics

Nature Communications ◽

10.1038/s41467-021-23553-7 ◽

2021 ◽

Vol 12 (1) ◽

Author(s):

Ling Xu ◽

Zhaobin Dong ◽

Dawn Chiniquy ◽

Grady Pierroz ◽

Siwen Deng ◽

...

Keyword(s):

Drought Stress ◽

Iron Metabolism ◽

Iron Transport ◽

Iron Homeostasis ◽

Molecular Mechanisms ◽

Microbial Community Composition ◽

Rna Seq ◽

Highly Correlated ◽

Root Microbiome

AbstractRecent studies have demonstrated that drought leads to dramatic, highly conserved shifts in the root microbiome. At present, the molecular mechanisms underlying these responses remain largely uncharacterized. Here we employ genome-resolved metagenomics and comparative genomics to demonstrate that carbohydrate and secondary metabolite transport functionalities are overrepresented within drought-enriched taxa. These data also reveal that bacterial iron transport and metabolism functionality is highly correlated with drought enrichment. Using time-series root RNA-Seq data, we demonstrate that iron homeostasis within the root is impacted by drought stress, and that loss of a plant phytosiderophore iron transporter impacts microbial community composition, leading to significant increases in the drought-enriched lineage, Actinobacteria. Finally, we show that exogenous application of iron disrupts the drought-induced enrichment of Actinobacteria, as well as their improvement in host phenotype during drought stress. Collectively, our findings implicate iron metabolism in the root microbiome’s response to drought and may inform efforts to improve plant drought tolerance to increase food security.

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