Ricerc@Sapienza

The goal of this proposal is to define the role of Histone Deacetylase 4 (HDAC4) in the regulation of the synthesis and/or secretion of soluble factors which affect muscle regeneration in Duchenne Muscular Dystrophy (DMD), with the aim of improving the therapy for this disease.
Background/Rationale. DMD is a genetic disorder characterized by progressive muscle weakness and degeneration. To date, no cure is available for this disease. The pan-HDAC inhibitor givinostat is presently in phase III clinical trial for the treatment of DMD since in a phase II study it showed improvement of histological features. However, as a general-HDAC-inhibitor, givinostat nonspecifically blocks all HDAC members, and long-term treatment with pan-HDACi has been associated with numerous side effects. HDAC4 mediates several stress responses in skeletal muscle as previously reported in satellite cell biology and muscle regeneration. Importantly, HDAC4 from skeletal muscle mediates the secretion of soluble factors upon injury, yet undefined, which inhibit the differentiation of muscle precursors. Since HDAC4 functions in DMD are still unclear, in order to investigate the HDAC4 role in DMD with a genetic approach, we generated mdx mice with a deletion of HDAC4, specifically in skeletal muscle. Our preliminary data suggest that HDAC4 deletion in skeletal muscle leads to earlier and exacerbated muscle degeneration in mdx mice. Moreover, it mediates the release of soluble factors from skeletal muscle, which severely affects healthy satellite cells (SC) proliferation and differentiation.
Here we propose to identify the soluble factors modulated by HDAC4 responsible for impairing SC proliferation and differentiation in DMD.