Improving the effects of HDAC8 inhibition by combining the activation of SIRT1 in a zebrafish model of Duchenne muscular dystrophy

Duchenne muscular dystrophy (DMD) is a genetic disease leading to rapid muscle degeneration. To date, the major strategy for therapeutic interventions is the pharmacological administration of compounds that reduce muscle loss, inflammation, and fibrosis. Among them, histone deacetylase (HDAC) inhibitors are currently in clinical trial phase III. In this project, we propose to compare the effect of the specific inhibition of HDAC8, which we found acting on cytoskeleton remodeling in DMD, with the activation of SIRTUIN1 that is able to restore the impaired mitochondrial metabolism in DMD skeletal muscle. We propose to test the combination treatments using dmd zebrafish embryos, a quick and cheap model that recapitulates the skeletal muscle phenotype of human with DMD. Our results will allow for optimizing the effects of single drugs alone, facilitating the discovery of novel pharmacological settings for individuals with DMD