Transferrin receptor 1 (Tfr1) is a widely expressed protein that mediates cellular iron uptake through receptor-mediated endocytosis of Fe-transferrin. Tfr1-/- embryos die in mid-gestation from ineffective erythropoiesis, precluding assessment of roles of Tfr1 later in development and after birth. To determine whether Tfr1 is important in other tissues, we developed a conditional (floxed) Tfr1 mouse model that allows for inactivation of the Tfr1 gene in cells expressing transgenic Cre recombinase from tissue- specific promoters. We focused on skeletal and cardiac muscle because both tissues are highly metabolic and require iron for myoglobin production, mitochondrial biogenesis and mitochondrial function. Our preliminary results indicate that Tfr1 is critically important in both skeletal muscle and heart, and suggest an unanticipated link between iron homeostasis and energy metabolism. In our first Aim, we will characterize a severe phenotype observed in mice lacking Tfr1 in skeletal muscle, to understand how Tfr1 and iron transport contribute to muscle development, muscle iron homeostasis, mitochondrial biogenesis and regulation of energy metabolism. In our second Aim, we will perform similar studies to elucidate the role of Tfr1 in the heart, an organ in which iron balance must be tightly regulated to maintain constant, high-level function while avoiding deleterious effects of iron deficiency and iron overload.

Public Health Relevance

Skeletal and heart muscle require more iron than most tissues because they need to produce energy for the work they do. They differ in several ways - heart muscle is working continuously and sensitive to too much or too little iron;skeletal muscle is used intermittently and is sensitive to iron deficiency but not iron overload. Little is known about how iron enters either type of muscle cell. This project takes advantage of unique mouse mutants, engineered in the Andrews laboratory, to learn about muscle iron transport and its relationship to heart failure, diabetes, and muscle diseases.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK089705-03
Application #
8507217
Study Section
Cardiovascular Differentiation and Development Study Section (CDD)
Program Officer
Bishop, Terry Rogers
Project Start
2011-07-01
Project End
2015-06-30
Budget Start
2013-07-01
Budget End
2014-06-30
Support Year
3
Fiscal Year
2013
Total Cost
$329,524
Indirect Cost
$119,636
Name
Duke University
Department
Pharmacology
Type
Schools of Medicine
DUNS #
044387793
City
Durham
State
NC
Country
United States
Zip Code
27705
Xu, Wenjing; Barrientos, Tomasa; Andrews, Nancy C (2013) Iron and copper in mitochondrial diseases. Cell Metab 17:319-28
Andrews, Nancy C (2012) Closing the iron gate. N Engl J Med 366:376-7