P.1.8 Genetic ablation of p66Shc rescues functional and morphological abnormalities in collagen VI dystrophic mice

Several studies documented the key role of abnormal production of reactive oxygen species (ROS) in the pathophysiology of muscular dystrophies (MDs) that are contributed also by mitochondrial dysfunction. The sources of ROS, however, are still controversial as well as their major molecular targets. This study investigated whether ROS produced in mitochondria by p66 Shc contributes to MD pathogenesis. p66 Shc is a growth factor adapter that is phosphorylated upon oxidative stress. In this form, a fraction of p66shc localizes to mitochondria, where it binds to cytochrome c and acts as an oxidoreductase, generating ROS and leading to organelle dysfunction and cell death. We provide clear evidence that inactivation of the gene encoding for p66 Shc reduced ROS accumulation along with a beneficial effect on the dystrophic phenotype of Col6a1 −/− mice, a model of Bethlem myopathy and Ullrich congenital MD. Based upon our previous observations on oxidative damage of myofibrillar proteins in heart failure and MDs, we hypothesized that p66 Shc -dependent ROS formation might impair contractile function in dystrophic muscles. Indeed, oxidation of myofibrillar proteins, as probed by formation of disulphide cross-bridges in tropomyosin, was detected in Col6a1 −/− mice. Notably, genetic ablation of p66 Shc significantly reduced myofiber apoptosis and ameliorated muscle strength in Col6a1 −/− mice. These findings demonstrate a novel and determinant role of p66 Shc in MDs, adding evidence of the pivotal role of mitochondria and suggesting p66 Shc as a novel pharmacological target for the therapy of human ColVI myopathies.