G.P.201

Weakness and fatigability, typical features of Duchenne muscular dystrophy, are aggravated in mdx mice by a chronic exercise on horizontal treadmill (30 min running at 12 m/min twice a week). This protocol leads to a significant decrease in limb force vs. non-exercised mdx mice by grip test; preliminary results by torque recordings confirm this functional impairment. Parallel ex vivo studies show that the exercise increases the resistance to eccentric contraction in C57BL/10 wild-type (wt) extensor digitorum longus (EDL) muscles, while such an adaptation is not observed in mdx ones, which remain weaker than controls. In order to understand the molecular mechanisms underlying exercise susceptibility of mdx mice we investigated by quantitative real-time PCR the outcome of 4 (T4, 8 weeks of age) and 12 (T12; 16 weeks of age) weeks of either exercise or cage-based activity on a large set of genes in gastrocnemius muscle of mdx and wt mice. Basal expression of peroxisome-proliferator receptor γ coactivator 1a (PGC-1a) and sirtuin-1 is higher in mdx vs. wt at both ages. Exercise increases PGC-1a expression in wt, while in mdx mice T12 exercise down-regulates PGC-1a, sirtuin-1, PPARγ and the autophagy marker BNIP3. 16 week-old mdx mice show a basal over-expression of the slow-phenotype genes; T12 exercise fully contrasts this basal adaptation and the high expression of follistatin and myogenin, being ineffective in wt mice. Damage- and inflammation-related genes, such as NADPH-oxidase, TGFâ and TNF-a are overexpressed in mdx muscle in all conditions. In parallel the anti-inflammatory adiponectin is lower in T12 exercised mdx muscle. Then a chronic exercise with minor adaptive effects in wt muscle, contrasts compensatory changes in the benign mdx phenotype leading to a disequilibrium between protective and damaging signals and disclosing potential drug targets.