Intermittent reloading does not prevent iron availability decrease and hepcidin upregulation caused by hindlimb unloading

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.