Duchenne muscular dystrophy (DMD) causes progressive skeletal muscle degeneration and currently there are few therapeutic options. The identification of new drug targets and their validation in model systems of DMD could be a promising approach to make progress in finding new treatments for this lethal disease. Histone deacetylases (HDACs) play key roles in myogenesis and the therapeutic approach targeting HDACs in DMD is in an advanced phase of clinical trial. Here, we show that the expression of HDAC8, one of the members of the HDAC family, is increased in DMD patients and dystrophic zebrafish. The selective inhibition of HDAC8 with the PCI-34051 inhibitor rescues skeletal muscle defects, similarly to the treatment with the pan-HDAC inhibitor Givinostat. Through acetylation profile of zebrafish with HDAC8 dysregulation, we identified new HDAC8 targets involved in cytoskeleton organization such as tubulin that, when acetylated, is a marker of stable microtubules. Our work provides evidence of HDAC8 overexpression in DMD patients and zebrafish and supports its specific inhibition as a new valuable therapeutic approach in the treatment of this pathology.

Targeting HDAC8 to ameliorate skeletal muscle differentiation in Duchenne muscular dystrophy / M. Spreafico, M. Cafora, C. Bragato, D. Capitanio, F. Marasca, B. Bodega, C. De Palma, M. Mora, C. Gelfi, A. Marozzi, A. Pistocchi. - In: PHARMACOLOGICAL RESEARCH. - ISSN 1043-6618. - 170(2021 Aug), pp. 105750.1-105750.10. [10.1016/j.phrs.2021.105750]

Targeting HDAC8 to ameliorate skeletal muscle differentiation in Duchenne muscular dystrophy

M. Spreafico;M. Cafora;D. Capitanio;F. Marasca;B. Bodega;C. De Palma;C. Gelfi;A. Marozzi;A. Pistocchi
2021

Abstract

Duchenne muscular dystrophy (DMD) causes progressive skeletal muscle degeneration and currently there are few therapeutic options. The identification of new drug targets and their validation in model systems of DMD could be a promising approach to make progress in finding new treatments for this lethal disease. Histone deacetylases (HDACs) play key roles in myogenesis and the therapeutic approach targeting HDACs in DMD is in an advanced phase of clinical trial. Here, we show that the expression of HDAC8, one of the members of the HDAC family, is increased in DMD patients and dystrophic zebrafish. The selective inhibition of HDAC8 with the PCI-34051 inhibitor rescues skeletal muscle defects, similarly to the treatment with the pan-HDAC inhibitor Givinostat. Through acetylation profile of zebrafish with HDAC8 dysregulation, we identified new HDAC8 targets involved in cytoskeleton organization such as tubulin that, when acetylated, is a marker of stable microtubules. Our work provides evidence of HDAC8 overexpression in DMD patients and zebrafish and supports its specific inhibition as a new valuable therapeutic approach in the treatment of this pathology.
Duchenne muscular dystrophy; Givinostat; Givinostat Hydrochloride Hydrate (PubChem CID: 9804991); HDAC8; PCI-34051; PCI-34051 (PubChem CID:24753719); Zebrafish
Settore BIO/13 - Biologia Applicata
Settore BIO/12 - Biochimica Clinica e Biologia Molecolare Clinica
Settore BIO/11 - Biologia Molecolare
Settore BIO/14 - Farmacologia
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/2434/863682
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