Iron homeostasis in mammalian muscle

描述（由申请人提供）：转铁蛋白受体1 （Tfr1）是一种广泛表达的蛋白，通过受体介导的铁-转铁蛋白内吞作用介导细胞铁摄取。Tfr1-/-胚胎在妊娠中期因红细胞生成作用无效而死亡，因此无法评估Tfr1在发育后期和出生后的作用。为了确定Tfr1在其他组织中是否重要，我们建立了一个条件（固定）Tfr1小鼠模型，该模型允许从组织特异性启动子中表达转基因Cre重组酶的细胞中灭活Tfr1基因。我们专注于骨骼肌和心肌，因为这两种组织都是高度代谢的，需要铁来产生肌红蛋白、线粒体生物发生和线粒体功能。我们的初步结果表明，Tfr1在骨骼肌和心脏中都至关重要，并提示铁稳态和能量代谢之间存在意想不到的联系。在我们的第一个目标中，我们将描述在骨骼肌缺乏Tfr1的小鼠中观察到的严重表型，以了解Tfr1和铁转运如何促进肌肉发育，肌肉铁稳态，线粒体生物发生和能量代谢调节。在我们的第二个目标中，我们将进行类似的研究来阐明Tfr1在心脏中的作用，心脏是一个必须严格调节铁平衡以保持恒定，高水平功能的器官，同时避免铁缺乏和铁过载的有害影响。

DESCRIPTION (provided by applicant): 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.