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Abstract
Iron deficiency is the most common nutrition deficiency in the world. The manifestation ofiron deficiency includes but is not limited to cold intolerance and muscle weakness, which associates two major organs: brown adipose tissue (BAT) and skeletal muscle.
BAT can be thermogenically activated under stimuli, such as b-adrenergic agonist and cold exposure. The activated BAT specializes in nonshivering thermogenesis to promote body temperature and consume energy. Whether BAT engages in iron deficiency induced cold intolerance and whether iron participates in BAT activation in unknown. Here we report that BAT activation induced TfR1-mediated iron uptake. Iron ion and transferrin receptor 1 (TfR1) were required for the thermogenic activation of BAT. Iron deprivation or TfR1 ablation in brown adipocyte dampened uncoupling respiration and blocked BAT mediated energy expenditure. On the contrary, iron supplement is sufficient to activate brown adipocyte without adrenergic stimuli. Mechanistically, iron catalyzed hydroxyl radical production via Fenton’s reaction and further induced lipid peroxidation during brown adipocyte activation in mitochondria. Neutralization of
hydroxyl radical or lipid peroxidation blocked the BAT activation induced by iron. Our data indicates that chelatable iron plays critical roles in activating thermogenesis of BAT, which expands the physiological functions of iron in metabolism and provides an explanation of iron deficiency associated cold intolerance.
Iron deficiency is also highly associated with skeletal muscle dysfunction. Skeletal muscle possesses the great potential to regenerate upon injury by satellite cells. The life-long maintenance of muscle tissue is orchestrated by satellite cell-mediated muscle regeneration. The biological function of iron in skeletal muscle regeneration and satellite cells activity remains largely unknown. Our study shows that deprivation of iron impaired the proliferation of satellite cells both in vitro and in vivo and jeopardized skeletal muscle regeneration. Iron depletion stabilized hypoxia-induced factor 2 (HIF2α) in the nuclei, further blocking satellite cell proliferation via Rb1/E2F pathway. Moreover, pharmacological inhibition of HIF2α by PT-2385 improved muscle regeneration in iron deficient mice. Overall, our findings demonstrate a critical function of iron in muscle regeneration through HIF2α-Rb1/E2F signaling and provide a therapeutically target to promote muscle regeneration for iron deficient population.