Effects of iron overload on gene expression in the cardiac and skeletal muscle of mice. Mus musculus

Hereditary Hemochromatosis (HH) is an autosomal recessive disorder characterized by an abnormally low expression or functional derangement of the iron regulatory hormone hepcidin. The absorption of dietary iron is disproportionate in these patients, leading to iron deposition in several tissues and consequent damage of organs including liver, heart, and pancreas. Late complications in absence of diagnosis and treatment include cirrhosis, hepatocellular carcinoma, cardiomyopathy and diabetes. Unfortunately, iron overload appears also as an acquired complication. This is the case of a variety of anemias (thalassemias, myelodysplastic syndromes, hemoglobinopathies, etc.) in which compensating mechanisms increase iron absorption. Another cause of iron overload in these patients are the repeated transfusional treatments they receive. It follows that iron overload is a common clinical problem. Therefore, we investigated the effects of iron overload on gene expression in skeletal muscle and heart using microarray technology. Genes with up-regulated expression after iron overload in both skeletal and heart muscle included angiopoietin-like 4, pyruvate dehydrogenase kinase 4 and calgranulin A and B. The expression of transferrin receptor, heat shock protein 1B and DnaJ homolog B1 were down-regulated by iron in both muscle types. Two potential hepcidin regulatory genes, hemojuvelin and neogenin, showed no clear change in expression after iron overload. Concluding, microarray analysis revealed iron-induced changes in the expression of several genes involved in the regulation of glucose and lipid metabolism, transcription and cellular stress responses. These may represent novel connections between iron overload and pathological manifestations of HH such as cardiomyopathy and diabetes. Keywords: iron induced stress response Overall design: C57 male mice were used following the next scheme: 2 diets (iron and control) 2 tissues (cardiac muscle and skeletal muscle) 3 biological replicates in each group That means the next groups of samples: 1. cardiac muscle from the iron loaded mice, 3 samples, one from each biological replicate 2. cardiac muscle from the control mice, 3 samples, one from each biological replicate 3. skeletal muscle from the iron loaded mice, 3 samples, one from each biological replicate 4. skeletal muscle from the control mice, 3 samples, one from each biological replicate There were 6 samples from each tissue type and a total of 12 samples in the study. The iron and control groups were compared for each tissue separately.