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.
The potential progress towards a therapeutic development for DMD is the long-term aim of this proposal. To date there is no effective cure for muscular dystrophies and more research must be done to further understand the molecular mechanisms underlying these pathologies. The pan-HDAC inhibitor givinostat has been shown to be partially beneficial for dystrophic mice and patients. However, givinostat was not able to improve adult dystrophic mouse phenotype or DMD patient muscle performance. Moreover, as a pan-HDACi, givinostat nonspecifically blocks all HDAC members and long-term treatment with pan-HDACi has been associated with numerous side effects.
Our results indicate that inhibition of class II HDAC4 in skeletal muscle is deleterious for skeletal muscle architecture in muscular dystrophy. Limiting the therapeutic approach to the use of class I HDAC inhibitors may still in part influences the acetylation status of HDAC4 targets, since HDAC4 deacetylates via class I HDACs.
By delineating the molecular functions of HDAC4 in DMD, and specifically in muscle necrosis, we aim to provide experimental basis for promoting HDAC4 specific targets or pathways, in combination with HDAC inhibitors, to ameliorate pharmacological treatments presently in use.