P3.43 Long term administration of green tea polyphenols and pentoxifylline to mdx5Cv dystrophic mice: differential effects on muscle function and kyphosis

DMD is a fatal muscle disorder caused by the absence of dystrophin and characterized by progressive muscle wasting. Weakness of the back muscles often causes postural alterations, impairing patients’ respiratory function. Oxidative stress likely contributes to the pathogenesis. We have previously shown that antioxidants such as green tea polyphenols (GTP) and EGCG (the major GTP component) improved muscle structure and function of the mdx5Cv mouse, a model for DMD. Pentoxifylline (PTX), a non-selective phosphodiesterase inhibitor and TNF α release inhibitor was used as a positive control and also proved efficacious. EGCG is about to be clinically evaluated on DMD patients. In this context, we investigated the effects on dystrophic mice of long-term oral administration (for 15 months, from 3-weeks to about 16-months of age) of GTP, EGCG, and PTX. As assessed at the end of the treatment period with a wire test (involving fore- and hind-limb force), the motor function was improved with the following potency: PTX > GTP > EGCG. Using micro-computed tomography, we determined that kyphosis, the characteristic spine deformity occurring in old dystrophic mice as a result of back and thorax muscle weakness, was prevented by GTP, to a lesser extent by EGCG, but not by PTX. Tomography also allowed us to identify calcifications of the Achilles tendons, which, to the best of our knowledge, have never been reported so far. These calcifications were about twice larger in dystrophic mice than in normal mice and were diminished with the following potency: GTP > EGCG ∼ PTX. Similarly, GTP and EGCG were more potent than PTX at reducing creatine kinase in the plasma (an index of muscle membrane fragility) and at preventing the loss of force induced by repetitive tetanic contractions. Our results suggest that GTP/EGCG and PTX exert different effects on different muscle groups. A combination of EGCG and PTX may provide more benefit than each compound alone.