Extreme physical inactivity affects differentially the iron metabolism in male and female rats

In humans, extreme physical inactivity (EPI) appears to differentially affect iron metabolism between sexes. Our objective was to understand the mechanisms involved in rats of both sexes exposed to hindlimb unloading (HU), an experimental model mimicking EPI. Eight-week-old male and female Wistar rats (n=12/group) underwent 7 days of HU, with control groups included. Serum, liver, spleen, and soleus muscle samples were collected. ICP-MS analyses were used to quantify iron concentration. Gene expression was analyzed by RT-qPCR and Western Blot.



In contrast to humans, control females exhibited higher serum iron availability, hepatic and spleen iron concentrations (HIC and SIC) than males. In HU males, serum iron availability was not affected, whereas there was an increase in serum hepcidin level, SIC, and HIC (p=0.001; p=0.023; p=0.003, respectively). Moreover, spleen and liver ferritin protein levels (FPL) increased (+60.9% and +134%, respectively; p<0.05), while TfR1 protein levels decreased (-50%; -35%, respectively; p<0.05). In HU females, there was no significant change in serum hepcidin level, LIC, SIC, and regarding TfR1 protein and FPL in spleen and liver. In HU males, concomitantly with SIC increase, heme oxygenase-1 mRNA level, a marker of RBC phagocytosis, increased (p<0.001). Paradoxically, it also increased in HU females (p<0.001). Alongside muscle atrophy observed in HU rodents, iron concentrations and FPL increased in the soleus in both sexes (p<0.001, p=0.047), and TfR1 protein was reduced (p<0.001), while muscle myoglobin protein and heme exporter FLVCR1 mRNA levels increased (p<0.001).



Our data suggest that EPI induces iron misdistribution only in males through accelerated erythrophagocytosis