Effect of forced and voluntary exercise on heart function in mice with low dystrophin levels

Duchenne muscular dystrophy patients lack dystrophin due to mutations in the X-chromosomal DMD gene. Patients develop severe heart failure, often leading to death. Several therapeutic approaches aiming at dystrophin restoration are in clinical trials, resulting in dystrophin restoration in skeletal muscle, while the heart appears more difficult to target. We here investigated the effects of different types of exercise on heart function and pathology in mice expressing low dystrophin levels (1–20%) in skeletal muscle and heart due to skewed X-inactivation (mdx-XistΔhs). We subjected 15.5 month old mdx-XistΔhs mice, mdx mice and two wild type mouse strains (C57BL/10ScSnJ and XistΔhs) to either treadmill running (twice weekly, 8 m/min 30 min), voluntary wheel running (total of 28 nights) or no exercise for a duration of 2 months. Ejection fraction, cardiac output, stroke volume and end-diastolic volume of the left and right ventricles and dilatation of the aortic arch were assessed at the age of 18 months. Additionally, fibrosis was visualized upon intravenous administration of the contrast solution Dotarem. Cardiac hypertrophy was observed in all mdx mice, regardless of the exercise regime, while this was prevented in a dystrophin level dependent manner in the mdx-XistΔhs mice. Collagen infiltration in the heart was also partly prevented in the mdx-XistΔhs mice, independently of the exercise type mdx-XistΔhsmice were subjected to. Expression levels of genes involved in heart function, immunological and fibrotic process assessments are pending. These data will unravel the consequences of low and high intensity exercise on heart function and pathology in mdx mice and highlight the protective effects of low dystrophin levels in the heart.