G.P.83

Dystrophin deficiency in mice (mdx) is the most commonly used animal model for Duchenne muscular dystrophy (DMD). Compared to DMD patients, mdx mice show a milder phenotype. The objective of this study was to assess the temporal alteration of paraclinical and clinical parameters over 18 months with a focus on sensitive, objective and investigator independent measurement methods in mdx animals. 3-weeks old mdx mice and C57BL/10 controls (WT) were placed in separate cages equipped with a running wheel for 2 weeks every 3 months. Voluntary wheel running parameters were recorded continuously 24 h per day. Cardiac ultrasound was performed every 3 months. After 18 months, animals were sacrificed. Blood and muscle were sampled for ex vivo muscle contraction tests, quantitative PCR and histological analysis. All mdx ran with a ∼ 50 % lower daily distance, max. velocity (vmax) and run time in the first 9 months compared to WT mice (mdx, 5 km; WT, 10 km per day). WT mice kept a similar vmax from month 12 to 18 but the distance declined gradually over time. mdx mice displayed a tremendous reduction of the distance and vmax during the last 9 months of the experiment. Twitch force and specific maximal tetanic force were not diminished in M. soleus of mdx compared to WT at 18 months. The same parameters were drastically reduced in the mdx diaphragm (DIA). After 300 s of sustained repetitive stimulation, mdx DIA displayed no relevant fatigability. mRNA-expression and staining of fiber types revealed a predominance of type I and IIa fibers in mdx DIA at 18 months. Echocardiography data will be demonstrated. In conclusion, we demonstrate the first life-long, longitudinal voluntary wheel assessment in combination with cardiac ultrasound of mdx compared to Bl10 mice. We show morphological and functional changes of mdx muscles with the most striking difference being fatigue resistance of DIA. Our data should be helpful for the future planning of preclinical treatment trials for DMD.