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.

A Red Carpet for Iron Metabolism

“…Genetic ablation of TFR1 in mice demonstrates the importance of the Tf endocytic cycle for iron import into erythroid cells (Levy et al, 1999) as well as cardiomyocytes (Xu et al, 2015), muscle cells (Barrientos et al, 2015), and dopaminergic neurons (Matak et al, 2016); combined immunodeficiency in patients with a Y20H substitution in TFR1 also reveals a role of TFR1 in B and T cells (Jabara et al, 2016). However, most non-erythroid tissues can develop without TFR1 (Li et al, 2009; Ned et al, 2003), showing that Tf-independent routes of iron acquisition exist.…”

Iron homeostasis: An anthropocentric perspective

“…Genetic deletion of TFR1 is embryonic lethal (62). Tissue-specific knockouts showed that TFR1 is required for normal iron metabolism in skeletal muscle (63) and cardiomyocytes (64) and that TFR1 serves an unidentified iron-independent function in intestinal epithelial cells (65). Transferrin receptor 2, largely restricted to the liver and erythroid precursors (66), also interacts with holotransferrin but does not substantially contribute to iron uptake (67), acting primarily as sensor of systemic iron status (41).…”

A role for iron deficiency in dopaminergic neurodegeneration

“…TfR1 deficiency in erythroid cells results in anemia caused by a hemoglobinization defect. In nonerythroid cells, iron defects resulting from TfR1 deficiency result in metabolic defects, defective mitophagy, and increase in gene expression associated with cell death (16,17). A noncanonical function for TfR1, not related to iron metabolism per se, has been recently reported in some tissues (15,18).…”

“…Loss of Fpn function in several cell types causes iron overload (11,12) and has been implicated in myelination defects (13). TfR1-mediated iron uptake is the main source of iron for actively proliferating cells, and is essential for iron transport in erythroid cells and neural tissue (14), epithelial enterocytes (15), skeletal muscle (16), and cardiac muscle (17), in addition to DA neurons, as described in Matak et al (6). TfR1 deficiency in erythroid cells results in anemia caused by a hemoglobinization defect.…”