The goal of this project is to define the role of Histone Deacetylase 4 (HDAC4) in satellite cells, with the aim of improving muscle regeneration in dystrophic conditions.
Background/Rationale. Muscular dystrophies are serious, often devastating and lethal, genetic disorders characterized by progressive muscle weakness and degeneration. Compromised muscle regeneration contributes to the progression of muscular dystrophy. Pan-HDAC inhibitors (HDACi), shown to improve muscle regeneration, are on clinical trial for the treatment of muscular dystrophy. However, long-term treatment with pan-HDACi provokes numerous side effects, likely due to their broad range of action. HDAC4 may play a pivotal role in muscular dystrophy: this is suggested by the change in its expression levels in dystrophic muscles and its involvement in satellite cell differentiation. A recent publication showed that HDAC4 is crucial for satellite cell commitment and differentiation; however, the underlying molecular mechanisms are still unidentified. We propose to identify HDAC4 direct transcriptional targets via biochemical and molecular analyses, by using genetic loss- and gain-of-function approaches. By manipulating HDAC4 targets we aim to promote satellite cell differentiation, bypassing some of the side effects of HDACi.
Anticipated output: our studies will provide experimental bases for the development of more effective drugs for treating muscular dystrophy.
Understanding the transcriptional targets controlled by HDAC4 in satellite cell renewal and differentiation will reveal new functions for HDAC4 in the regulation of skeletal muscle homeostasis. Moreover, promoting muscle differentiation bypassing HDAC4 inhibition will provide new insights for the development of new pharmaceutical approaches to combine with HDACi currently in use to ameliorate muscular dystrophies.
The potential progress towards a therapeutic development for muscular dystrophy 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. Pan-HDACi have been shown to be beneficial for dystrophic mice, by promoting muscle regeneration. However, HDACi nonspecifically block all HDAC members and long-term treatment has been associated with numerous side effects. 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. Our results indicate that inhibition of class II HDAC4 in skeletal stem cells is deleterious for proper satellite cell differentiation. By identifying the molecular functions and the direct targets of HDAC4 in satellite cells, we aim to manipulate HDAC4 specific targets or pathways, in combination with the inhibition of HDAC4, to ameliorate pharmacological treatments currently in use.