Ricerc@Sapienza

Histone Deacetylase 4 (HDAC4) is a member of class II HDACs that regulates many stress responses in skeletal muscle. Recently, its protective, essential role in maintaining skeletal muscle homeostasis after long-term denervation1 or in ALS2 and in satellite cell proliferation and differentiation3,4 has been clarified. Duchenne Muscular Dystrophy (DMD) is a devastating genetic disorder characterized by progressive muscle weakness, increased sarcolemma fragility and degeneration5.The membrane repair response, which involves multiple proteins such as dysferlin and TRIM72 is enhanced to maintain membrane integrity in DMD6. The pan-HDAC inhibitor givinostat showed improvement of DMD histological features in a phase-II study. However, no efficacy in improving muscle function has been registered, highlighting the need to study further the HDAC functions in skeletal muscle in DMD. To shed light on HDAC4 effects in skeletal muscle, we are studying the HDAC4 role in DMD. We generated DMD mice with HDAC4 deleted in skeletal muscle (mdx;HDAC4mKO), by crossing mice with a skeletal muscle-specific deletion of HDAC4 with mdx mice. To determine HDAC4 functions, pathology progression has been analyzed over time. HDAC4 deletion exacerbates muscle degeneration, and decreases muscle functionality over time. Further investigations highlighted impaired membrane repair in mdx;HDAC4mKO mice that may underpin the more pronounced progression of the pathology. The goal of this study is to define the molecular signaling modulated by HDAC4 in the membrane repair response in DMD in order to provide experimental basis for a more efficacious pharmacological therapy.
References:
1)Skelet Muscle 2018Feb 24;8(1):6;2)EBioMedicine2019Feb;40:717-732.3;3)Sci Rep2018Feb 22;8(1):3448;4)Front Physiol2018 Sep27;9:1387;5)PhysiolRev2002 Apr;82(2):291-329;6)Cell Death and diff2017 24,330-342; 7)Neuromuscul Disord2016Oct;26(10):643-649