title: Lethal Cardiomyopathy in Mice Lacking Transferrin Receptor in the Heart.
abstract: Both iron overload and iron deficiency have been associated with cardiomyopathy and heart failure, but cardiac iron utilization is incompletely understood. We hypothesized that the transferrin receptor (Tfr1) might play a role in cardiac iron uptake and used gene targeting to examine the role of Tfr1 in vivo. Surprisingly, we found that decreased iron, due to inactivation of Tfr1, was associated with severe cardiac consequences. Mice lacking Tfr1 in the heart died in the second week of life and had cardiomegaly, poor cardiac function, failure of mitochondrial respiration, and ineffective mitophagy. The phenotype could only be rescued by aggressive iron therapy, but it was ameliorated by administration of nicotinamide riboside, an NAD precursor. Our findings underscore the importance of both Tfr1 and iron in the heart, and may inform therapy for patients with heart failure.
authors.affiliation: Department of Pharmacology and Cancer Biology, Duke University School of Medicine, Duke University, Durham, NC 27705, USA.
authors.forename: Wenjing
authors.initials: W
authors.lastname: Xu
authors.affiliation: Department of Pharmacology and Cancer Biology, Duke University School of Medicine, Duke University, Durham, NC 27705, USA.
authors.forename: Tomasa
authors.initials: T
authors.lastname: Barrientos
authors.affiliation: Department of Medicine, Duke University School of Medicine, Duke University, Durham, NC 27705, USA.
authors.forename: Lan
authors.initials: L
authors.lastname: Mao
authors.affiliation: Department of Medicine, Duke University School of Medicine, Duke University, Durham, NC 27705, USA.
authors.forename: Howard A
authors.initials: HA
authors.lastname: Rockman
authors.affiliation: Department of Pharmacology, Weill Cornell Medical College, Cornell University, New York, NY 10065, USA.
authors.forename: Anthony A
authors.initials: AA
authors.lastname: Sauve
authors.affiliation: Department of Pharmacology and Cancer Biology, Duke University School of Medicine, Duke University, Durham, NC 27705, USA; Department of Pediatrics, Duke University School of Medicine, Duke University, Durham, NC 27705, USA. Electronic address: nancy.andrews@duke.edu.
authors.forename: Nancy C
authors.initials: NC
authors.lastname: Andrews
mesh_terms: D000818:Animals; D009202:Cardiomyopathies / Q000188:drug therapy / Q000235:genetics* / Q000473:pathology; D019069:Cell Respiration; D007501:Iron / Q000378:metabolism; D051379:Mice; D063306:Mitophagy; D009206:Myocardium / Q000378:metabolism* / Q000473:pathology; D009536:Niacinamide / Q000031:analogs & derivatives / Q000627:therapeutic use; D011726:Pyridinium Compounds; D011990:Receptors, Transferrin / Q000235:genetics* / Q000378:metabolism
chemical_list: D011726:Pyridinium Compounds; D011990:Receptors, Transferrin; C480029:Tfrc protein, mouse; C018613:nicotinamide-beta-riboside; D009536:Niacinamide; D007501:Iron