The discovery of hepcidin has provided a solid foundation for understanding the mechanisms of systemic iron homeostasis and the aetiologies of iron disorders. Hepcidin assures the balance of ...circulating and stored iron levels for multiple physiological processes including oxygen transport and erythropoiesis, while limiting the toxicity of excess iron. The liver is the major site where regulatory signals from iron, erythropoietic drive and inflammation are integrated to control hepcidin production. Pathologically, hepcidin dysregulation by genetic inactivation, ineffective erythropoiesis, or inflammation leads to diseases of iron deficiency or overload such as iron‐refractory iron‐deficiency anaemia, anaemia of inflammation, iron‐loading anaemias and hereditary haemochromatosis. In the present review, we discuss recent insights into the molecular mechanisms governing hepcidin regulation, how these pathways are disrupted in iron disorders, and how this knowledge is being used to develop novel diagnostic and therapeutic strategies.
Systemic iron homeostasis is regulated by the hepatic hormone hepcidin to balance meeting iron requirements while limiting toxicity from iron excess. Iron‐mediated induction of bone morphogenetic ...protein (BMP) 6 is a central mechanism for regulating hepcidin production. Liver endothelial cells (LECs) are the main source of endogenous BMP6, but how they sense iron to modulate BMP6 transcription and thereby hepcidin is uncertain. Here, we investigate the role of endothelial cell transferrin receptor 1 (TFR1) in iron uptake, BMP6 regulation, and systemic iron homeostasis using primary LEC cultures and endothelial Tfrc (encoding TFR1) knockout mice. We show that intracellular iron regulates Bmp6 expression in a cell‐autonomous manner, and TFR1 mediates iron uptake and Bmp6 expression by holo‐transferrin in primary LEC cultures. In addition, endothelial Tfrc knockout mice exhibit altered iron homeostasis compared with littermate controls when fed a limited iron diet, as evidenced by increased liver iron and inappropriately low Bmp6 and hepcidin expression relative to liver iron. However, endothelial Tfrc knockout mice have a similar iron phenotype compared to littermate controls when fed an iron‐rich standard diet. Finally, ferritin and non‐transferrin bound iron (NTBI) are additional sources of iron that mediate Bmp6 induction in primary LEC cultures via TFR1‐independent mechanisms. Together, our data demonstrate a minor functional role for endothelial cell TFR1 in iron uptake, BMP6 regulation, and hepatocyte hepcidin regulation under iron limiting conditions, and suggest that ferritin and/or NTBI uptake by other transporters have a dominant role when iron availability is high.
ABSTRACTRomero-Parra, N, Cupeiro, R, Alfaro-Magallanes, VM, Rael, B, Rubio-Arias, JA, Peinado, AB, and Benito, PJ, IronFEMME Study Group. Exercise-induced muscle damage during the menstrual cycleA ...systematic review and meta-analysis. J Strength Cond Res XX(X)000–000, 2020—A strenuous bout of exercise could trigger damage of muscle tissue, and it is not clear how sex hormone fluctuations occurring during the menstrual cycle (MC) affect this response. The aims of this study were to systematically search and assess studies that have evaluated exercise-induced muscle damage (EIMD) in eumenorrheic women over the MC and to perform a meta-analysis to quantify which MC phases display the muscle damage response. The guidelines of the Preferred Reported Items for Systematic Reviews and Meta-Analysis were followed. A total of 19 articles were analyzed in the quantitative synthesis. Included studies examined EIMD in at least one phase of the following MC phasesearly follicular phase (EFP), late follicular phase (LFP), or midluteal phase (MLP). The meta-analysis demonstrated differences between MC phases for delayed onset muscle soreness (DOMS) and strength loss (p < 0.05), whereas no differences were observed between MC phases for creatine kinase. The maximum mean differences between pre-excercise and post-exercise for DOMS were EFP6.57 (4.42, 8.71), LFP5.37 (2.10, 8.63), and MLP3.08 (2.22, 3.95), whereas for strength loss were EFP−3.46 (−4.95, −1.98), LFP−1.63 (−2.36, −0.89), and MLP−0.72 (−1.07, −0.36) (p < 0.001). In conclusion, this meta-analysis suggests that hormone fluctuations throughout the MC affect EIMD in terms of DOMS and strength loss. Lower training loads or longer recovery periods could be considered in the EFP, when sex hormone concentrations are lower and women may be more vulnerable to muscle damage, whereas strength conditioning loads could be enhanced in the MLP.
The bone morphogenetic protein (BMP)-SMAD signaling pathway plays a central role in regulating hepcidin, which is the master hormone governing systemic iron homeostasis. Hepcidin is produced by the ...liver and acts on the iron exporter ferroportin to control iron absorption from the diet and iron release from body stores, thereby providing adequate iron for red blood cell production, while limiting the toxic effects of excess iron. BMP6 and BMP2 ligands produced by liver endothelial cells bind to BMP receptors and the coreceptor hemojuvelin (HJV) on hepatocytes to activate SMAD1/5/8 signaling, which directly upregulates hepcidin transcription. Most major signals that influence hepcidin production, including iron, erythropoietic drive, and inflammation, intersect with the BMP-SMAD pathway to regulate hepcidin transcription. Mutation or inactivation of BMP ligands, BMP receptors, HJV, SMADs or other proteins that modulate the BMP-SMAD pathway result in hepcidin dysregulation, leading to iron-related disorders, such as hemochromatosis and iron refractory iron deficiency anemia. Pharmacologic modulators of the BMP-SMAD pathway have shown efficacy in pre-clinical models to regulate hepcidin expression and treat iron-related disorders. This review will discuss recent insights into the role of the BMP-SMAD pathway in regulating hepcidin to control systemic iron homeostasis.
•BMP-SMAD signaling has a central role in iron homeostasis by regulating hepcidin.•Iron and erythropoietic drive modulate BMP-SMAD signaling to regulate hepcidin.•Inflammation requires BMP-SMAD signaling for maximal hepcidin induction.•Aberrant BMP-SMAD signaling and hepcidin levels contribute to many iron disorders.•The BMP-SMAD pathway and hepcidin are therapeutic targets for treating iron disorders.
The aim of this study was to evaluate whether the menstrual cycle and its underlying hormonal fluctuations affect muscle damage and inflammation in well-trained females following an eccentric ...exercise. Nineteen eumenorrheic women performed an eccentric squat-based exercise in the early follicular phase, late follicular phase and mid-luteal phase of their menstrual cycle. Sex hormones and blood markers of muscle damage and inflammation -creatine kinase, myoglobin, lactate dehydrogenase, interleukin-6, tumoral necrosis factor-, and C reactive protein- were analyzed in each phase. No effect of menstrual cycle phase was observed (
> 0.05), while an interaction for interleukin-6 was shown (
= 0.047). Accordingly, a moderate effect size 0.68 (0.53)-0.84 (0.74), indicated that interleukin-6 values 2 h post-trial (2.07 1.26 pg/mL) were likely to be higher than baseline (1.59 0.33 pg/mL), 24 h (1.50 0.01 pg/mL) and 48 h (1.54 0.13 pg/mL) in the mid-luteal phase. Blood markers of muscle damage and inflammation were not affected by the menstrual cycle in well-trained women. The eccentric exercise barely triggered muscle damage and hence, no inflammation was observed, possibly due to participants training status. The mid-luteal phase was the only phase reflecting a possible inflammatory response in terms of interleukin-6, although further factors than sex hormones seem to be responsible for this finding.
The use of oral contraceptives (OCs) by female athletes may lead to improved iron status, possibly through the regulation of hepcidin by sex hormones. The present work investigates the response of ...hepcidin and interleukin‐6 (IL‐6) to an interval exercise in both phases of the OC cycle. Sixteen endurance‐trained OC users (age 25.3 ± 4.7 years; height 162.4 ± 5.7 cm; body mass 56.0 ± 5.7 kg; body fat percentage 24.8 ± 6.0%; peak oxygen consumption VO2peak: 47.4 ± 5.5 mL min−1 kg−1) followed an identical interval running protocol during the withdrawal and active pill phases of the OC cycle. This protocol consisted of 8 × 3 minutes bouts at 85% VO2peak speed with 90 seconds recovery intervals. Blood samples were collected pre‐exercise, and at 0 hour, 3 hours, and 24 hours post‐exercise. Pre‐exercise 17β‐estradiol was lower (P = .001) during the active pill than the withdrawal phase (7.91 ± 1.81 vs 29.36 ± 6.45 pg/mL mean ± SEM). No differences were seen between the OC phases with respect to hepcidin or IL‐6 concentrations, whether taking all time points together or separately. However, within the withdrawal phase, hepcidin concentrations were higher at 3 hours post‐exercise (3.33 ± 0.95 nmol/L) than at pre‐exercise (1.04 ± 0.20 nmol/L; P = .005) and 0 hour post‐exercise (1.41 ± 0.38 nmol/L; P = .045). Within both OC phases, IL‐6 was higher at 0 hour post‐exercise than at any other time point (P < .05). Similar trends in hepcidin and IL‐6 concentrations were seen at the different time points during both OC phases. OC use led to low 17β‐estradiol concentrations during the active pill phase but did not affect hepcidin. This does not, however, rule out estradiol affecting hepcidin levels.
Purpose
To assess the influence of different hormonal profiles on the cardiorespiratory response to exercise in endurance-trained females.
Methods
Forty-seven eumenorrheic females, 38 low-dose ...monophasic oral contraceptive (OC) users and 13 postmenopausal women, all of them endurance-trained, participated in this study. A DXA scan, blood sample tests and a maximal aerobic test were performed under similar low-sex hormone levels: early follicular phase for the eumenorrheic females; withdrawal phase for the OC group and at any time for postmenopausal women. Cardiorespiratory variables were measured at resting and throughout the maximal aerobic test (ventilatory threshold 1, 2 and peak values). Heart rate (HR) was continuously monitored with a 12-lead ECG. Blood pressure (BP) was measured with an auscultatory method and a calibrated mercury sphygmomanometer. Expired gases were measured breath-by-breath with the gas analyser Jaeger Oxycon Pro.
Results
One-way ANCOVA reported a lower peak HR in postmenopausal women (172.4 ± 11.7 bpm) than in eumenorrheic females (180.9 ± 10.6 bpm) (
p
= 0.024). In addition, postmenopausal women exhibited lower VO
2
(39.1 ± 4.9 ml/kg/min) compared to eumenorrheic females (45.1 ± 4.4 ml/kg/min) in ventilatory threshold 2 (
p
= 0.009). Nonetheless, respiratory variables did not show differences between groups at peak values. Finally, no differences between OC users and eumenorrheic females’ cardiorespiratory response were observed in endurance-trained females.
Conclusions
Cardiorespiratory system is impaired in postmenopausal women due to physiological changes caused by age and sex hormones’ decrement. Although these alterations appear not to be fully compensated by exercise, endurance training could effectively mitigate them. In addition, monophasic OC pills appear not to impact cardiorespiratory response to an incremental running test in endurance-trained females.
•Hepatocyte TfR1 requires HFE for its role in hepcidin regulation and iron homeostasis.•Hepatocyte TfR1 restrains hepcidin induction by serum iron and promotes hepcidin suppression and iron overload ...in β-thalassemia.
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Transferrin receptor 1 (TfR1) performs a critical role in cellular iron uptake. Hepatocyte TfR1 is also proposed to influence systemic iron homeostasis by interacting with the hemochromatosis protein HFE to regulate hepcidin production. Here, we generated hepatocyte Tfrc knockout mice (Tfrcfl/fl;Alb-Cre+), either alone or together with Hfe knockout or β-thalassemia, to investigate the extent to which hepatocyte TfR1 function depends on HFE, whether hepatocyte TfR1 impacts hepcidin regulation by serum iron and erythropoietic signals, and its contribution to hepcidin suppression and iron overload in β-thalassemia. Compared with Tfrcfl/fl;Alb-Cre− controls, Tfrcfl/fl;Alb-Cre+ mice displayed reduced serum and liver iron; mildly reduced hematocrit, mean cell hemoglobin, and mean cell volume; increased erythropoietin and erythroferrone; and unchanged hepcidin levels that were inappropriately high relative to serum iron, liver iron, and erythroferrone levels. However, ablation of hepatocyte Tfrc had no impact on iron phenotype in Hfe knockout mice. Tfrcfl/fl;Alb-Cre+ mice also displayed a greater induction of hepcidin by serum iron compared with Tfrcfl/fl;Alb-Cre− controls. Finally, although acute erythropoietin injection similarly reduced hepcidin in Tfrcfl/fl;Alb-Cre+ and Tfrcfl/fl;Alb-Cre− mice, ablation of hepatocyte Tfrc in a mouse model of β-thalassemia intermedia ameliorated hepcidin deficiency and liver iron loading. Together, our data suggest that the major nonredundant function of hepatocyte TfR1 in iron homeostasis is to interact with HFE to regulate hepcidin. This regulatory pathway is modulated by serum iron and contributes to hepcidin suppression and iron overload in murine β-thalassemia.
Hepcidin is the master regulator of systemic iron homeostasis. Using genetically manipulated murine models, Xiao and colleagues reveal that hepatocyte transferrin receptor 1 (TfR1) restrains hepcidin induction by serum iron and promotes hepcidin suppression and iron overload in β-thalassemia. The authors prove that TfR1 action is dependent upon HFE, the product of the most commonly mutated gene in hereditary hemochromatosis, adding important detail to our knowledge of iron regulation.
The aim of the current study was to investigate iron metabolism in endurance trained women through the interleukin-6, hepcidin and iron responses to exercise along different endogenous hormonal ...states. Fifteen women performed 40 min treadmill running trials at 75% vVO2peak during three specific phases of the menstrual cycle: early follicular phase (day 3 ± 0.85), mid-follicular phase (day 8 ± 1.09) and luteal phase (day 21 ± 1.87). Venous blood samples were taken pre-, 0 h post- and 3 h post-exercise. Interleukin-6 reported a significant interaction for menstrual cycle phase and time (p=0.014), showing higher interleukin-6 levels at 3 h post-exercise during luteal phase compared to the early follicular phase (p=0.004) and the mid-follicular phase (p=0.002). Iron levels were significantly lower (p=0.009) during the early follicular phase compared to the mid-follicular phase. However, hepcidin levels were not different across menstrual cycle phases (p>0.05). The time-course for hepcidin and interleukin-6 responses to exercise was different from the literature, since hepcidin peak levels occurred at 0 h post-exercise, whereas the highest interleukin-6 levels occurred at 3 h post-exercise. We concluded that menstrual cycle phases may alter interleukin-6 production causing a higher inflammation when progesterone levels are elevated (days 19-21). Moreover, during the early follicular phase a significant reduction of iron levels is observed potentially due to a loss of haemoglobin through menses. According to our results, high intensity exercises should be carefully monitored in these phases in order not to further compromise iron stores.
•Bmp5-mutant mice have low hepcidin in early life and exhibit mild iron loading under low- or high-iron or Bmp6-heterozygous conditions.•Bmp5 mutations exacerbate hemochromatosis and abrogate ...hepcidin responses to iron in Bmp6-knockout mice.
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Hepcidin is the master regulator of systemic iron homeostasis. The bone morphogenetic protein (BMP) signaling pathway is a critical regulator of hepcidin expression in response to iron and erythropoietic drive. Although endothelial-derived BMP6 and BMP2 ligands have key functional roles as endogenous hepcidin regulators, both iron and erythropoietic drives still regulate hepcidin in mice lacking either or both ligands. Here, we used mice with an inactivating Bmp5 mutation (Bmp5se), either alone or together with a global or endothelial Bmp6 knockout, to investigate the functional role of BMP5 in hepcidin and systemic iron homeostasis regulation. We showed that Bmp5se-mutant mice exhibit hepcidin deficiency at age 10 days, blunted hepcidin induction in response to oral iron gavage, and mild liver iron loading when fed on a low- or high-iron diet. Loss of 1 or 2 functional Bmp5 alleles also leads to increased iron loading in Bmp6-heterozygous mice and more profound hemochromatosis in global or endothelial Bmp6-knockout mice. Moreover, double Bmp5- and Bmp6-mutant mice fail to induce hepcidin in response to long-term dietary iron loading. Finally, erythroferrone binds directly to BMP5 and inhibits BMP5 induction of hepcidin in vitro. Although erythropoietin suppresses hepcidin in Bmp5se-mutant mice, it fails to suppress hepcidin in double Bmp5- and Bmp6-mutant males. Together, these data demonstrate that BMP5 plays a functional role in hepcidin and iron homeostasis regulation, particularly under conditions in which BMP6 is limited.
Hepcidin is the master regulator of iron homeostasis and is regulated by bone morphogenetic protein (BMP) signaling in response to iron loading, iron deficiency, and erythropoietic drive. This regulation is largely a reflection of BMP6 and BMP2, but the role of BMP5 has not been defined. Xiao et al probed the contribution of BMP5 signaling to iron homeostasis, demonstrating that it also has a role in hepcidin regulation. BMP6 heterozygous or homozygous-null mice have increased iron loading that is further amplified with concomitant BMP5 knockout. This further elucidates the complex process of hepcidin regulation and iron metabolism.
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