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

Abstract

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.

Simulated microgravity disturbs iron metabolism and distribution in humans: Lessons from dry immersion, an innovative ground‐based human model

“…Using the hind limb unloading (HU) model to simulate the microgravity in rats, we recently showed that short‐term exposure to HU causes iron misdistribution, characterized by increased splenic iron store 8 . Interestingly, hepatic hepcidin expression and blood hepcidin levels increase in rodents exposed to simulated microgravity 8‐10 . As hepcidin controls iron release from cells, especially spleen macrophages, it could play a key role in microgravity‐induced iron misdistribution by limiting the expression and activity of ferroportin, the cell iron exporter that allows iron recycling from macrophages in plasma 11 .…”

Métabolisme du fer : impact de l’hypoactivité et mécanismes sous-jacents

“…Afin de répondre en partie au premier objectif précédemment énoncé, nous avons relancé un protocole de suspension par la queue sur une période plus longue de 14 jours. Nous avons ainsi observé que la rate n'était plus surchargée en fer sur une période plus longue d'hypoactivité, malgré une réduction persistante de la biodisponibilité du fer [31]. Ces résultats suggèrent donc que le fer est toujours anormalement distribué à plus long terme, mais que les organes impactés…”

“…c c e p t e d m a n u s c r i p t ne sont pas nécessairement les mêmes. Le foie et le muscle squelettique atrophié ne seraient pas les cibles de cette surcharge au regard de l'absence de changements des concentrations en fer chez les animaux suspendus par la queue[31]. De manière intéressante, des travaux conduit parallèlement aux nôtres ont observé chez le rongeur que le foie et l'os commencent à être surchargés en fer après une plus longue période d'hypoactivité (i.e.…”

“…Ensemble, ces résultats soulignent que la redistribution du fer se produisant en hypoactivité est dynamique dans le temps et affecte de manière différenciée nos organes. La séquestration de fer splénique se produisant à court terme pourrait ainsi constituer un mécanisme de protection préservant d'autres organes comme le foie et l'os d'une surcharge délétère en fer, ce mécanisme n'étant à priori plus efficace lorsque l'exposition à l'hypoactivité se prolonge.Dans cette étude, nous avons également observé que les niveaux d'ARNm codant pour l'hepcidine restaient élevés dans le foie après 14 jours de suspension[31]. D'un côté, l'activation de la voie IL-6/STAT3 n'est plus visible suggérant que l'état pro-inflammatoire se réduit progressivement avec l'adaptation de l'organisme à son nouvel environnement.…”

Experimental Physiology special issue: Extreme environmental physiology

“…Hindlimb unloading is one of the models employed to study the effects of microgravity on musculo‐skeletal physiology. Nay and colleagues address the question of whether skeletal muscle is involved in microgravity‐induced iron misdistribution by modulating the expression of hepcidin, and whether intermittent reloading is of benefit in this regard (Nay et al., 2021). One of the major, as yet unsolved, problems to be faced by those exposed to long periods of microgravity is the visual disturbances collectively known as space flight‐associated neuro‐ocular syndrome (SANS).…”