Cardiorespiratory abnormalities in early and advances stage mouse models of Duchenne muscular dystrophy

Abstract

Duchenne muscular dystrophy (DMD) is an X-linked severe muscle disease caused by dystrophin gene mutations affecting 1 in 3,500 newborn males worldwide every year. DMD is characterized by progressive skeletal muscle degeneration and weakness. In advanced disease, respiratory insufficiency and dilated cardiomyopathy limit life expectancy. The purpose of this study was to investigate the time course of myocardial fibrosis and respiratory decline in a mouse model of DMD. The extent of fibrosis was determined in histological sections using planimetry. We found that 16-month-old DMD hearts were in early stages of myocardial fibrosis, with 9.6 +/- 0.04 percent in the RV (n=3) and 2.1 +/- 0.01 percent in the LV (n=3). In contrast, the dystrophic changes in the diaphragm at 16 months of age were severe (52.1 percent fibrosis). Using wholebody plethysmography and pulse oximetry, we assessed respiratory function and blood oxygen saturation (SaO2). At 12 months of age, Dmdmdx4cv mice exhibited significantly lower respiratory frequency and oxygen consumption. However, ventilation (Ve) and ventilatory equivalent (Ve/VCO2) were not different compared to wild-type littermates, in part due to slightly increased tidal volume. Likewise, there was no effect of genotype on SaO2. These data suggest that while the dystrophic changes in the diaphragm were severe, overall respiratory status is not severely compromised in 12--16-month-old DMD mice. Altogether, these data provide a framework for determining the time course of cardiorespiratory decline in DMD mice. In the future, this could lead to new therapeutic approaches to minimize DMD-induced heart and respiratory failure at early-stage disease.