In humans, exposure to microgravity during spaceflights causes muscle atrophy, iron storage changes, and iron availability reduction. We previously observed in rats that during simulated microgravity for 7 days, hepcidin plays a key role in iron misdistribution, and suggested that a crosstalk between skeletal muscle and liver could regulate hepcidin synthesis in this context. In the present study, we investigated in rats the medium-term effects of simulated microgravity on iron metabolism. We also tested whether intermittent reloading (IR) to target skeletal muscle atrophy efficiently limits iron misdistribution. To this purpose, Wistar rats underwent 14 days of hindlimb unloading (HU) combined or not with daily IR. At the end of this period, serum iron concentration and transferrin saturation were significantly reduced, whereas hepatic hepcidin mRNA was upregulated. However, the main signaling pathways involved in hepcidin synthesis in liver (BMP/SMAD, IL6/STAT3, and ERK1/2) were unaffected. Differently from what observed after 7 days of HU, iron concentration in spleen, liver and skeletal muscle was comparable between control and animals that underwent HU or HU+IR for 14 days. Despite its beneficial effect on soleus muscle atrophy and slow-to-fast myosin heavy chain distribution, IR did not significantly prevent iron availability reduction and hepcidin upregulation. Altogether, these results highlight that iron availability is durably reduced during longer exposure to simulated microgravity, and that the related hepcidin upregulation is not a transient adaptation to this condition. They also suggest that skeletal muscle does not necessarily play a key role in iron misdistribution occurring during simulated microgravity. NEW FINDINGS What is the central question of this study? Could skeletal muscle be involved in microgravity-induced iron misdistribution by modulating hepcidin expression, the master regulator of iron metabolism? What is the main finding and its importance? We demonstrate in rats that hepcidin upregulation is not a transient adaptation associated with early exposure to microgravity, and that intermittent reloading does not limit microgravity-induced iron misdistribution despite a beneficial effect on soleus muscle wasting.

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