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International audience; BACKGROUND: Iron metabolism imbalance could contribute to physical deconditioning experienced by astronauts due to its essential role in energy metabolism, cellular respiration, and oxygen transport. OBJECTIVES: In this clinical exploratory study, we wanted to determine whether artificial gravity (AG) training modulated iron metabolism, red blood cell indices, and body lean mass in male and female healthy participants exposed to head-down tilt (HDT) bed rest, the reference ground-based model of microgravity. METHODS: We recruited 8 female and 16 male healthy participants who were all exposed to HDT bed rest for 60 days. In addition, they were assigned to three experimental groups (n = 8/each): controls, continuous AG training in a short-arm centrifuge (1×30 min/day), and intermittent AG training (6 × 5 min/day). RESULTS: The iron metabolism responses to simulated microgravity of AG training groups do not significantly differ from the responses of controls. Independently from AG, we found that both serum iron (+31.3%, P = 0.027) and transferrin saturation levels (+28.4%, P = 0.009) increased in males after 6 days of HDT bed rest, as well as serum hepcidin levels (+36.9% P = 0.005). The increase of transferrin saturation levels persisted after 57 days of HDT bed rest (+13.5%, P = 0.026), suggesting that long-term exposure to microgravity sustainably increases serum iron availability in males, and consequently the risk of iron excess or misdistribution. In females, 6 and 57 days of HDT bed rest did not significantly change serum iron, transferrin saturation, and hepcidin levels. CONCLUSIONS: The data from this exploratory study suggest that 1) AG training does not influence the iron metabolism responses to microgravity; 2) iron metabolism parameters, especially iron availability for cells, are significantly increased in males, but not in females, exposed to long-term simulated microgravity. Due to the small sample size of females, we nevertheless must be cautious before concluding that iron metabolism could differently respond to microgravity in females. Clinical trial registry number: DRKS00015677.

Pierre Brissot,1 Thibault Cavey,1,2 Martine Ropert,1,2 Pascal Guggenbuhl,1,3 Olivier Loréal1 1Inserm UMR991, 2Laboratory of Biochemistry, 3Department of Rheumatology, University Hospital, Rennes, France Abstract: Hemochromatosis (HC) corresponds to systemic iron overload of genetic origin. Its spectrum covers HFE-related HC, a frequent disease exclusively present in Caucasians; however, several entities of non-HFE-related HC, which correspond to very rare disorders, have been observed in both Caucasian and non-Caucasian populations. In most HC forms, iron overload is explained by hepcidin deficiency, which increases iron delivery into the plasma from both duodenal and splenic sources, with subsequent organ iron deposition. The diagnosis depends on a noninvasive approach combining clinical, biological, and imaging data. The treatment remains largely based on phlebotomy therapy, which is rarely replaced with erythrocytapheresis or chelation therapy. Hepcidin supplementation represents the logical therapeutics of the future for all HC forms related to hepcidin deficiency. Keywords: iron overload, HFE, ferroportin, hemojuvelin, transferrin receptor 2, hepcidin, phlebotomy

Thanks to the discovery of the HFE gene and of its mutations, it is now established that the most frequent form of hemochromatosis is related to homozygosity for the mutation C282Y, and that other types of hemochromatosis, unrelated to HFE mutations, do exist such as the juvenile hemochromatosis. From a pathophysiological standpoint, the C282Y mutation impairs HFE protein expression at the surface of the membrane and disturbs the cellular entry of iron (carried by circulating transferrin) into the cryptic duodenal cell. This, in turn, is likely to lead to an aberrant programmation of the degree of iron influx from the digestive lumen into the apical duodenal cells. The resulting hyperabsorption, which forms the basis of iron overload in hemochromatosis, is likely to implicate an overexpression of the transmembrane iron carrier DMT1. It is remarkable to observe that these major improvements in the knowledge of hemochomatosis have been accompanied by similar improvements in the understanding of normal iron metabolism.

The hepatic extracellular matrix is involved in both the stability of liver architecture and the hepatic function. Fibrogenesis occurs during various chronic liver diseases. It is the consequence of an imbalance between synthesis, deposition and degradation of extracellular matrix components leading to fibrosis and, then, cirrhosis. Hepatic stellate cells are the main source of extracellular matrix components in fibrogenesis. Among the factors involved in fibrogenesis, transforming growth factor beta 1 plays a central role. The vascular and cellular consequences of liver fibrogenesis require new specific diagnostic and therapeutic strategies.