Ricerc@Sapienza

The goal of this project is to define the role of Histone Deacetylase 4 (HDAC4) in Duchenne Muscular Dystrophy (DMD), with particular reference to muscle necrosis and degeneration, in order to improve pharmacological treatments presently in use for DMD.
Background/Rationale. DMD is a devastating, genetic disorder characterized by progressive muscle weakness and degeneration. To date, no cure is available for this disease. The general HDAC inhibitor (HDACi) givinostat is presently in phase III clinical trial for the treatment of DMD, since in a phase II study showed improvement of histological features. However, several limitations are associated with the use of HDACi. HDAC4 is a member of class II HDACs that regulates satellite cell biology and muscle regeneration. Its expression is up-regulated in skeletal muscle of mdx mice, a murine model for studying DMD, suggesting a role in this disease. However, HDAC4 functions in DMD are still unclear.
To investigate HDAC4 role in DMD with a genetic approach, we generated mdx mice with a deletion of HDAC4, specifically in skeletal muscle. From our preliminary data HDAC4 deletion in skeletal muscle anticipates and exacerbates muscle degeneration in mdx mice.
Here we plan to better characterize the dystrophic phenotype in mice with skeletal muscle deletion of HDAC4 and to define the signaling modulated by HDAC4 in DMD by NGS analysys.
Anticipated output. By defining HDAC4 functions, our studies will provide the experimental bases for the development of more effective drugs for treating muscular dystrophy.