Genetic hemochromatosis is an iron overload disease that is mainly related to the C282Y mutation in the HFE gene. This gene controls the expression of hepcidin, a peptide secreted in plasma by the liver and regulates systemic iron distribution. Homozygous C282Y mutation induces hepcidin deficiency, leading to increased circulating transferrin saturation, and ultimately, iron accumulation in organs such as the liver, pancreas, heart, and bone. Iron in excess may induce or favor the development of complications such as cirrhosis, liver cancer, diabetes, heart failure, hypogonadism, but also complaints such as asthenia and disabling arthritis. Iron depletive treatment mainly consists of venesections that permit the removal of iron contained in red blood cells and the subsequent mobilization of stored iron in order to synthesize hemoglobin for new erythrocytes. It is highly efficient in removing excess iron and preventing most of the complications associated with excess iron in the body. However, this treatment does not target the biological mechanisms involved in the iron metabolism disturbance. New treatments based on the increase of hepcidin levels, by using hepcidin mimetics or inducers, or inhibitors of the iron export activity of ferroportin protein that is the target of hepcidin, if devoid of significant secondary effects, should be useful to better control iron parameters and symptoms, such as arthritis.

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.

Hereditary aceruloplasminemia (HA), related to mutations in the ceruloplasmin (Cp) gene, leads to iron accumulation. Ceruloplasmin ferroxidase activity being considered essential for macrophage iron release, macrophage iron overload is expected, but it is not found in hepatic and splenic macrophages in humans. Our objective was to get a better understanding of the mechanisms leading to iron excess in HA. A clustered regularly interspaced short palindromic repeats (CRISPR)/ CRISPR associated protein 9 (Cas9) knockout of the Cp gene was performed on Sprague-Dawley rats. We evaluated the iron status in plasma, the expression of iron metabolism genes, and the status of other metals whose interactions with iron are increasingly recognized. In Cp 2/2 rats, plasma ceruloplasmin and ferroxidase activity were absent, together with decreased iron concentration and transferrin saturation. Similarly as in humans, the hepatocytes were iron overloaded conversely to hepatic and splenic macrophages. Despite a relative hepcidin deficiency in Cp 2/2 rats and the loss of ferroxidase activity, potentially expected to limit the interaction of iron with transferrin, no increase of plasma non-transferrin-bound iron level was found. Copper was decreased in the spleen, whereas manganese was increased in the plasma. These data suggest that the reported role of ceruloplasmin cannot fully explain the iron hepatosplenic phenotype in HA, encouraging the search for additional mechanisms.-

IL-6 is an axial cytokine overexpressed in cancer to promote growth and increase resistance to anti-cancer therapies. As the application of IL-6-targeting therapies are still limited, alternative non-aggressive and adjuvant approaches, like physical activity (PA) could be useful to reverse IL-6 effects. To get more insights into liposarcoma (LS) pathophysiology, we investigated potential molecular links between IL-6 and LS growth and we tested the impact of PA on such mechanism in an orthotopic model of intramuscular LS. Initially active nude mice have received an intramuscular injection of either human SW872 cells or vehicle, then were respectively randomized into voluntary-active or inactive mice with open or restricted access to activity-wheels. We found that LS-bearing mice exhibited ∼6 fold increase in circulating IL-6 comparing to controls, with a concomitant decrease in hepatic drug-metabolizing enzymes expression. Circulating IL-6 levels were positively correlated with intra-tumor IL-6 expression (r = 0.85, P < 0.01). Interestingly, intra-tumor IL-6, C/EBP-α/β and PPAR-γ expression were correlated together and with greater tumor mass and autophagy markers, notably, GABARAPL-1. Intriguingly, we found that maintaining a spontaneous PA after tumor injection did not reduce the levels of IL-6, but even enhanced tumor growth, induced body weight loss and increased the risk of developing lung metastasis. Our findings suggest that (1) IL-6, C/EBP-β and PPAR-γ exert a potential role in promoting growth of dedifferentiated LS and (2) that PA failed to mechanistically interfere with these factors, but enhanced LS growth via other independent-mechanisms. The preclinical data reported here could be helpful in the sub-molecular classification of LS patients to improve diagnosis and design a low-risk treatment. Circulating IL-6 could serve as an indicator for treatment follow-up and, perhaps, for infra-radiologic LS relapses.