Grants and Contributions:

Grant or Award spanning more than one fiscal year. (2017-2018 to 2022-2023)

Mammalian dietary iron absorption and body iron traffic are controlled by hepcidin, a liver-derived peptide hormone. Hepcidin binds to the iron exporter ferroportin in target cells and promotes its degradation, thereby inhibiting iron flux into the bloodstream. The expression of hepcidin requires hemojuvelin (Hjv), a bone morphogenetic protein (BMP) co-receptor. Hjv operates by enhancing iron-dependent BMP/SMAD signaling to hepcidin in the liver, the major site of hepcidin production. Liver-specific disruption of either hepcidin or Hjv leads to severe iron overload. Both hepcidin and Hjv are also expressed in other tissues, where they may exert localized functions. Hjv is highly abundant in the heart and skeletal muscles. By generating liver- and muscle-specific Hjv-/- mice, we demonstrated that only liver Hjv regulates systemic iron homeostasis.
The objective of this proposal is to characterize the function of Hjv in the heart and skeletal muscles. In preliminary data we provide evidence that cardiac Hjv acts as a suppressor (rather than enhancer) of local hepcidin expression. We also show that skeletal muscles are spared from iron overload in Hjv-/- mice.
We hypothesize that cardiac Hjv is crucial for the control of heart iron metabolism especially under hypoxia, while skeletal muscle Hjv exhibits an iron-independent function in tissue repair. To address these hypotheses, we will perform biochemical studies with cultured cardiomyocytes, and characterize cardiac iron metabolism in tissue-specific Hjv-/- mice. Moreover, we will investigate the roles of Hjv and hepcidin in cardiac iron metabolism and function under physiological conditions or under hypoxia. Finally, we will explore a possible role of Hjv in skeletal muscle regeneration following injury.
The proposal builds on our previous work and is supported by preliminary data. We are undertaking biochemical, physiological and genetic approaches. Critical reagents and tools are in hand. Our laboratory is the only one possessing muscle-specific Hjv-/- mice with cardiac disruption of Hjv, which places us in a unique position to accomplish the proposed work. Implementation of this project will provide important insights on the biochemical and physiological functions of Hjv in the heart and in skeletal muscles, which are largely unexplored.