Ricerc@Sapienza

Histone deacetylase 4 (HDAC4) is a stress responsive factor that mediates multiple responses in skeletal muscle upon different stresses. We have clarified its protective role in maintaining skeletal muscle homeostasis after denervation, or in Amyotrophic Lateral Sclerosis, and in muscle regeneration upon injury. As a member of class IIa, HDAC4 shuttles from the nucleus to the cytoplasm in response to several stimuli. We have found HDAC4 to be upregulated prevalently in the cytoplasm of Duchenne Muscular Dystrophy (DMD) muscles in humans and mice. DMD is a genetic, progressive, incurable disorder, characterized by muscle degeneration and weakness. To delineate HDAC4 role in skeletal muscle in DMD, we generated and characterized mdx mice with a tissue-specific deletion of HDAC4 (mdx;KO). We demonstrated that deletion of HDAC4 in skeletal muscle worsens the pathological features of DMD, by enhancing muscle damage and reducing muscle regeneration, ultimately leading to a decrease in muscle performance. We proved that the mdx;KO phenotype is rescued by the cytoplasmic HDAC4 (HDAC4 L/A). Considering its protective role in mdx;KO muscles, we delivered HDAC4 L/A in mdx muscles via electroporation, ameliorating mdx muscle function and architecture. We propose to fully characterize the effects of cytoplasmic HDAC4 L/A in DMD in terms of muscle function, degeneration, regeneration, and lipid infiltration. Our results will provide innovative findings and suggestions for new pharmacological approaches (i.e. delivery of cytoplasmic HDAC4 or pharmacological extrusion of HDAC4 from the nucleus) for the treatment of DMD patients.