Commonly used cardiac-specific mouse models of FA utilize the muscle creatine kinase (MCK) promoter to express Cre recombinase in cardiomyocytes and striated muscle cells in mice with one conditional Fxn allele and one floxed-out/null allele. These mice quickly develop cardiomyopathy that becomes fatal by 9-11 weeks of age. Here, the authors generated a cardiac-specific model with floxed Fxn allele homozygosity (MCK-Fxnflox/flox). MCK-Fxnflox/flox mice were phenotypically normal at 9 weeks of age, despite no detectable FXN protein expression. Between 13 and 15 weeks of age, these mice began to display progressive cardiomyopathy, including decreased ejection fraction and fractional shortening, and increased left ventricular mass. MCK-Fxnflox/flox mice began to lose weight around 16 weeks of age, characteristically associated with heart failure in other cardiac-specific FA models. By 18 weeks of age, MCK-Fxnflox/flox mice displayed elevated markers of Fe-S deficiency, cardiac stress and injury, and cardiac fibrosis. This modified model reproduced important pathophysiological and biochemical features of FA over a longer timescale than previous cardiac-specific mouse models, offering a larger window for studying potential therapeutics.

Read More Here