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
The potential progress towards improving the current therapeutic approaches for the treatment of DMD is the long-term aim of this proposal. To date, no effective cure for DMD is available, and more research must be done to understand further the molecular mechanisms underlying this pathology. The pan-HDAC inhibitor givinostat has been shown to be partially beneficial for dystrophic mice and patients. However, givinostat was not able to improve the dystrophic phenotype in adult mice or muscle performance in DMD patients. 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.
If, as we speculate, HDAC4 mediates membrane stability in DMD and the ectopic expression of Trim72 will rescue mdx;HDAC4mKO phenotype in vivo, we will provide preclinical evidence of proposing combined treatment with HDACi for DMD therapy. Trim72 protein administration has been proposed as a treatment for DMD 1. Preclinical studies demonstrated that Trim72 administration improves muscle integrity and membrane stability overall reducing muscle necrosis and ameliorating muscle homeostasis in mouse 2 and hamster model 3 of DMD. As a long-term goal of this project, a combined treatment of givinostat with Trim72 recombinant protein may be proposed to counteract the pathology progression in DMD patients.
References: 1) Sci. Transl. Med. 4, 139ra85 (2012); 2) Sci Transl Med. 2012 Jun 20;4(139):139ra85; 3) Mol. Ther. 20, 727¿735 (2012).