[en] NEW FINDINGS: What is the central question of this study? Although microgravity is well known to reduce circulating iron in astronauts, the underlying mechanism is still unknown. We investigated whether hepcidin, a key hormone regulating iron metabolism, could be involved in this deleterious effect. What is the main finding and its importance? We show that hindlimb suspension, a model of microgravity, stimulates the production of hepcidin in liver of rats. In agreement with the biological role of hepcidin, we found a decrease of circulating iron and an increase of spleen iron content in hindlimb-unloaded rats. Consequently, our study supports the idea that hepcidin could play a role in the alteration of iron metabolism parameters observed during spaceflight. During spaceflight, humans exposed to microgravity exhibit an increase of iron storage and a reduction of circulating iron. Such perturbations could promote oxidative stress and anaemia in astronauts. The mechanism by which microgravity modulates iron metabolism is still unknown. Herein, we hypothesized that microgravity upregulates hepcidin, a hormone produced by the liver that is the main controller of iron homeostasis. To test this hypothesis, rats were submitted to hindlimb unloading (HU), the reference model to mimic the effects of microgravity in rodents. After 7 days, the mRNA level of hepcidin was increased in the liver of HU rats (+74%, P = 0.001). In agreement with the biological role of hepcidin, we found an increase of spleen iron content (+78%, P = 0.030) and a decrease of serum iron concentration (-35%, P = 0.002) and transferrin saturation (-25%, P = 0.011) in HU rats. These findings support a role of hepcidin in microgravity-induced iron metabolism alteration. Furthermore, among the signalling pathways inducing hepcidin mRNA expression, we found that only the interleukin-6/signal transducer and activator of transcription 3 (IL-6/STAT3) axis was activated by HU, as shown by the increase of phospho-STAT3 (+193%, P < 0.001) and of the hepatic mRNA level of haptoglobin (+167%, P < 0.001), a STAT3-inducible gene, in HU rats. Taken together, these data support the idea that microgravity may alter iron metabolism through an inflammatory process upregulating hepcidin.
Disciplines :
Biochemistry, biophysics & molecular biology
Author, co-author :
Cavey, Thibault ✱
Pierre, Nicolas ✱; Université de Liège - ULiège > Département des sciences cliniques > Hépato-gastroentérologie
Nay, Kevin
Allain, Coralie
Ropert, Martine
Loreal, Olivier
Derbre, Frederic
✱ These authors have contributed equally to this work.
Language :
English
Title :
Simulated microgravity decreases circulating iron in rats: role of inflammation-induced hepcidin upregulation.
Publication date :
2017
Journal title :
Experimental Physiology
ISSN :
0958-0670
eISSN :
1469-445X
Publisher :
Blackwell, Oxford, United Kingdom
Volume :
102
Issue :
3
Pages :
291-298
Peer reviewed :
Peer Reviewed verified by ORBi
Commentary :
(c) 2017 The Authors. Experimental Physiology (c) 2017 The Physiological Society.
Alonzi T, Maritano D, Gorgoni B, Rizzuto G, Libert C & Poli V (2001). Essential role of STAT3 in the control of the acute-phase response as revealed by inducible gene inactivation [correction of activation] in the liver. Mol Cell Biol 21, 1621-1632
Barry M & Sherlock S (1971). Measurement of liver-iron concentration in needle-biopsy specimens. Lancet 1, 100-103
Bosutti A, Malaponte G, Zanetti M, Castellino P, Heer M, Guarnieri G & Biolo G (2008). Calorie restriction modulates inactivity-induced changes in the inflammatory markers C-reactive protein and pentraxin-3. J Clin Endocrinol Metab 93, 3226-3229
Caron AZ, Drouin G, Desrosiers J, Trensz F & Grenier G (2009). A novel hindlimb immobilization procedure for studying skeletal muscle atrophy and recovery in mouse. J Appl Physiol 106, 2049-2059
Core AB, Canali S & Babitt JL (2014). Hemojuvelin and bone morphogenetic protein (BMP) signaling in iron homeostasis. Front Pharmacol 5, 104.
Crucian BE, Zwart SR, Mehta S, Uchakin P, Quiriarte HD, Pierson D, Sams CF & Smith SM (2014). Plasma cytokine concentrations indicate that in vivo hormonal regulation of immunity is altered during long-duration spaceflight. J Interferon Cytokine Res 34, 778-786
Ganz T (2011). Hepcidin and iron regulation, 10 years later. Blood 117, 4425-4433
Globus RK & Morey-Holton E (2016). Hindlimb unloading: rodent analog for microgravity. J Appl Physiol 120, 1196-1206
Hargens AR & Vico L (2016). Long-duration bed rest as an analog to microgravity. J Appl Physiol 120, 891-903
Judge AR, Koncarevic A, Hunter RB, Liou HC, Jackman RW & Kandarian SC (2007). Role for IκBα, but not c-Rel, in skeletal muscle atrophy. Am J Physiol Cell Physiol 292, C372-C382.
Kwon OS, Tanner RE, Barrows KM, Runtsch M, Symons JD, Jalili T, Bikman BT, McClain DA, O’Connell RM & Drummond MJ (2015). MyD88 regulates physical inactivity-induced skeletal muscle inflammation, ceramide biosynthesis signaling, and glucose intolerance. Am J Physiol Endocrinol Metab 309, E11-E21.
Mehta SK, Laudenslager ML, Stowe RP, Crucian BE, Sams CF & Pierson DL (2014). Multiple latent viruses reactivate in astronauts during Space Shuttle missions. Brain Behav Immun 41, 210-217
Memoli B, Salerno S, Procino A, Postiglione L, Morelli S, Sirico ML, Giordano F, Ricciardone M, Drioli E, Andreucci VE & Bartoli LD (2010). A translational approach to micro-inflammation in end-stage renal disease: molecular effects of low levels of interleukin-6. Clin Sci (Lond) 119, 163-174
Morgan JL, Zwart SR, Heer M, Ploutz-Snyder R, Ericson K & Smith SM (2012). Bone metabolism and nutritional status during 30-day head-down-tilt bed rest. J Appl Physiol 113, 1519-1529
Mutin-Carnino M, Carnino A, Roffino S & Chopard A (2014). Effect of muscle unloading, reloading and exercise on inflammation during a head-down bed rest. Int J Sports Med 35, 28-34
Pierre N, Deldicque L, Barbé C, Naslain D, Cani PD & Francaux M (2013). Toll-like receptor 4 knockout mice are protected against endoplasmic reticulum stress induced by a high-fat diet. PLoS One 8, e65061.
Poli M, Luscieti S, Gandini V, Maccarinelli F, Finazzi D, Silvestri L, Roetto A & Arosio P (2010). Transferrin receptor 2 and HFE regulate furin expression via mitogen-activated protein kinase/extracellular signal-regulated kinase (MAPK/Erk) signaling. Implications for transferrin-dependent hepcidin regulation. Haematologica 95, 1832-1840
Ramey G, Deschemin JC & Vaulont S (2009). Cross-talk between the mitogen activated protein kinase and bone morphogenetic protein/hemojuvelin pathways is required for the induction of hepcidin by holotransferrin in primary mouse hepatocytes. Haematologica 94, 765-772
Reardon TF & Allen DG (2009). Iron injections in mice increase skeletal muscle iron content, induce oxidative stress and reduce exercise performance. Exp Physiol 94, 720-730
Salaun E, Lefeuvre-Orfila L, Cavey T, Martin B, Turlin B, Ropert M, Loreal O & Derbre F (2016). Myriocin prevents muscle ceramide accumulation but not muscle fiber atrophy during short-term mechanical unloading. J Appl Physiol 120, 178-187
Schaap CC, Hendriks JC, Kortman GA, Klaver SM, Kroot JJ, Laarakkers CM, Wiegerinck ET, Tjalsma H, Janssen MC & Swinkels DW (2013). Diurnal rhythm rather than dietary iron mediates daily hepcidin variations. Clin Chem 59, 527-535
Smith SM, Zwart SR, Block G, Rice BL & Davis-Street JE (2005). The nutritional status of astronauts is altered after long-term space flight aboard the International Space Station. J Nutr 135, 437-443
Stowe RP, Sams CF & Pierson DL (2011). Adrenocortical and immune responses following short-and long-duration spaceflight. Aviat Space Environ Med 82, 627-634
Tavassoli M (1982). Anemia of spaceflight. Blood 60, 1059-1067
Tsay J, Yang Z, Ross FP, Cunningham-Rundles S, Lin H, Coleman R, Mayer-Kuckuk P, Doty SB, Grady RW, Giardina PJ, Boskey AL & Vogiatzi MG (2010). Bone loss caused by iron overload in a murine model: importance of oxidative stress. Blood 116, 2582-2589
Xu X, Tan C, Li P, Zhang S, Pang X, Liu H, Li L, Sun X, Zhang Y, Wu H, Chen X & Ge Q (2013). Changes of cytokines during a spaceflight analog-a 45-day head-down bed rest. PLoS One 8, e77401.
Yamaki T, Wu CL, Gustin M, Lim J, Jackman RW & Kandarian SC (2012). Rel A/p65 is required for cytokine-induced myotube atrophy. Am J Physiol Cell Physiol 303, C135-C142.
Zhang AS (2010). Control of systemic iron homeostasis by the hemojuvelin-hepcidin axis. Adv Nutr 1, 38-45
Zhao N, Zhang AS & Enns CA (2013). Iron regulation by hepcidin. J Clin Invest 123, 2337-2343
Zwart SR, Crawford GE, Gillman PL, Kala G, Rodgers AS, Rogers A, Inniss AM, Rice BL, Ericson K, Coburn S, Bourbeau Y, Hudson E, Mathew G, Dekerlegand DE, Sams CF, Heer MA, Paloski WH & Smith SM (2009a). Effects of 21 days of bed rest, with or without artificial gravity, on nutritional status of humans. J Appl Physiol 107, 54-62
Zwart SR, Morgan JL & Smith SM (2013). Iron status and its relations with oxidative damage and bone loss during long-duration space flight on the International Space Station. Am J Clin Nutr 98, 217-223
Zwart SR, Oliver SA, Fesperman JV, Kala G, Krauhs J, Ericson K & Smith SM (2009b). Nutritional status assessment before, during, and after long-duration head-down bed rest. Aviat Space Environ Med 80, A15-A22.
