Background: Duchenne muscular dystrophy (DMD) is a genetic disorder resulting in marked reduction or absence of the sarcolemmal protein dystrophin. In the majority of DMD patients, progressive skeletal muscle wasting is accompanied by development of cardiac abnormalities, leading to dilated cardiomyopathy and finally heart failure. Duchenne associated cardiomyopathy has been little investigated so far, especially the interaction of function and metabolism is almost unexplored. MDX mice are a common model for muscular dystophy (e.g., Duchenne muscular dystrophy). Therefore, we aimed to analyze cardiac function, with focus on metabolism and mitochondrial function, and characterized the severity of Duchenne-associated cardiomyopathy in MDX-mice of different ages.

Methods: MDX (C57BL/10ScSn-Dmdmdx/J) and control (C57BL/10ScSnJ) mice were examined at the age of 6, 12 and 18 months (mo). Cardiac function and morphology was assessed by echocardiography. Cardiac mitochondria were isolated and maximal respiratory capacity was measured. Cardiac metabolism was assessed in the isolated working heart.

Results: MDX mice showed only a mild phenotype. No externally recognizable differences to control mice were found. However, exercise tests revealed significant limitations in running time and distance (18mo: control 425m vs. MDX 216m; p≤0,05). MDX mice present with normal body weight but increased heart weight leading to significantly elevated heart-to-body weight ratio at all investigated time points (12mo: 4,2±0,2 vs. 5,1±0,1; p≤0,05). Echocardiography revealed significant hypertrophy of the left ventricle at 12 month, but normal systolic and diastolic function at all time points (18mo ejection fraction: 52,7±2,3 vs. 54,2±2,5%). In contrast to the left ventricle, the right ventricle showed obvious signs of dysfunction. We found an enlargement of the right ventricle and the right atrium at the age of 12 month (3,8±0,4 vs. 5,3±0,4mm²; p≤0,05). And also a deterioration of right ventricular function, assessed as TAPSE, in the MDX mice, which was significant at 6 and 18 months (6mo: 0,71±0,05 vs. 0,57±0,02mm; p≤0,05). In heart homogenate, activity of the mitochondrial enzyme citrate synthase was decreased at 12 and 18 months. In isolated cardiac mitochondria, respiratory capacity (ADP-stimulated respiration with different substrates) was also impaired at 12 and 18 months (12mo glutamate/malate: 442±78 vs. 191±22natomsO/min/mg; p≤0,05). In the isolated working heart, basal glucose oxidation, fatty acid oxidation and insulin stimulated oxidation rates were not different between MDX and control mice at all time points. There was only a slight decrease of ex vivo cardiac power in the MDX mice.