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.
