T.P.4.04 Tamoxifen improves the structure and the function of skeletal muscle in mdx mice

Data from the literature indicate that tamoxifen (Tam), a selective estrogen receptor modulator (SERM) used in the treatment of certain types of breast cancers, displays antioxidant, anti-apoptotic and anti-fibrotic properties and stabilises biological membranes. We hypothesised that Tam might improve both the structure and the function of dystrophic muscles. When applied to primary cultures of dystrophic myotubes, Tam and 4-hydroxy-Tam (10−8 to 10−6 M) were not toxic, reduced collagen content slightly, and exhibited a limited antioxidant activity against hydrogen peroxide. Mdx dystrophic mice, the most common model for Duchenne muscular dystrophy, were treated for about 15 months following weaning with 0.01% tamoxifen mixed into the food pellets (Tam intake approx. 10 mg/kg/day). Tam-treated mdx mice showed a significant decrease in body weight, likely due to the important reduction in white adipose tissue compared to untreated mice. The mass of the triceps surae (composed of soleus, plantaris and gastrocnemius muscles) was lowered to normal values, while the EDL and the diaphragm showed significant hypertrophy compared with both normal and untreated dystrophic animals. Using the horizontal wire test, the Tam-treated mdx performed as well as the normal mice and three times better than the untreated mdx mice. Isometric muscle force of the triceps surae was recorded. Remarkably, specific phasic and tetanic twitch tensions were increased by 100% and 70%, respectively, compared with untreated mdx, resulting in values higher than those of normal animals. The rates of contraction and relaxation were much slower than in the untreated mdx, and the force–frequency curve was significantly shifted to the left, suggesting a marked change toward a slower phenotype. In the Tam-treated mdx, the resistance to repetitive tetanisations was improved by 44% and creatine kinase levels were lowered by 50% compared with the untreated mdx. On-going histological analysis suggests a normalisation of the mean fiber diameter.