title: Metabolic Catastrophe in Mice Lacking Transferrin Receptor in Muscle.
abstract: Transferrin receptor (Tfr1) is ubiquitously expressed, but its roles in non-hematopoietic cells are incompletely understood. We used a tissue-specific conditional knockout strategy to ask whether skeletal muscle required Tfr1 for iron uptake. We found that iron assimilation via Tfr1 was critical for skeletal muscle metabolism, and that iron deficiency in muscle led to dramatic changes, not only in muscle, but also in adipose tissue and liver. Inactivation of Tfr1 incapacitated normal energy production in muscle, leading to growth arrest and a muted attempt to switch to fatty acid β oxidation, using up fat stores. Starvation signals stimulated gluconeogenesis in the liver, but amino acid substrates became limiting and hypoglycemia ensued. Surprisingly, the liver was also iron deficient, and production of the iron regulatory hormone hepcidin was depressed. Our observations reveal a complex interaction between iron homeostasis and metabolism that has implications for metabolic and iron disorders.
authors: Department of Pharmacology and Cancer Biology, Duke University School of Medicine, Durham, NC 27710, USA.
authors: Tomasa
authors: T
authors: Barrientos
authors: Department of Pharmacology and Cancer Biology, Duke University School of Medicine, Durham, NC 27710, USA.
authors: Indira
authors: I
authors: Laothamatas
authors: Molecular Physiology Institute, Sarah W. Stedman Nutrition and Metabolism Center, Duke University, Durham, NC 27704, USA; Department of Medicine, Duke University School of Medicine, Durham, NC 27710, USA.
authors: Timothy R
authors: TR
authors: Koves
authors: Duke Proteomics and Metabolomics Shared Resource, Center for Genomic and Computational Biology, Duke University School of Medicine, Durham, NC 27710, USA; Department of Cell Biology, Duke University School of Medicine, Durham, NC 27710, USA.
authors: Erik J
authors: EJ
authors: Soderblom
authors: Department of Pharmacology and Cancer Biology, Duke University School of Medicine, Durham, NC 27710, USA.
authors: Miles
authors: M
authors: Bryan
authors: Duke Proteomics and Metabolomics Shared Resource, Center for Genomic and Computational Biology, Duke University School of Medicine, Durham, NC 27710, USA.
authors: M Arthur
authors: MA
authors: Moseley
authors: Department of Pharmacology and Cancer Biology, Duke University School of Medicine, Durham, NC 27710, USA; Molecular Physiology Institute, Sarah W. Stedman Nutrition and Metabolism Center, Duke University, Durham, NC 27704, USA; Department of Medicine, Duke University School of Medicine, Durham, NC 27710, USA.
authors: Deborah M
authors: DM
authors: Muoio
authors: Department of Pharmacology and Cancer Biology, Duke University School of Medicine, Durham, NC 27710, USA; Department of Pediatrics, Duke University School of Medicine, Durham, NC 27710, USA.
authors: Nancy C
authors: NC
authors: Andrews
mesh_terms: D000818:Animals; D016000:Cluster Analysis; D005786:Gene Expression Regulation; D005804:Genes, Lethal; D000090463:Iron Deficiencies; D019189:Iron Metabolism Disorders / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D008099:Liver / Q000378:metabolism; D055442:Metabolome; D055432:Metabolomics / Q000379:methods; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D018482:Muscle, Skeletal / Q000378:metabolism / Q000473:pathology; D009132:Muscles / Q000378:metabolism* / Q000473:pathology; D010085:Oxidative Phosphorylation; D010641:Phenotype; D011990:Receptors, Transferrin / Q000172:deficiency* / Q000235:genetics
chemical_list: D011990:Receptors, Transferrin
keywords: Hepcidin; Intermediary metabolism; Iron; Skeletal muscle; Transferrin receptor