PUBLICATION

Targeting HDAC8 to ameliorate skeletal muscle differentiation in Duchenne muscular dystrophy

Authors
Spreafico, M., Cafora, M., Bragato, C., Capitanio, D., Marasca, F., Bodega, B., De Palma, C., Mora, M., Gelfi, C., Marozzi, A., Pistocchi, A.
ID
ZDB-PUB-210703-45
Date
2021
Source
Pharmacological research   170: 105750 (Journal)
Registered Authors
Keywords
Duchenne muscular dystrophy, Givinostat, Givinostat Hydrochloride Hydrate (PubChem CID: 9804991), HDAC8, PCI-34051, PCI-34051 (PubChem CID:24753719), zebrafish
MeSH Terms
  • Acetylation
  • Animals
  • Animals, Genetically Modified
  • Cell Differentiation*
  • Disease Models, Animal
  • Histone Deacetylase Inhibitors/pharmacology*
  • Histone Deacetylases/genetics
  • Histone Deacetylases/metabolism
  • Humans
  • Hydroxamic Acids/pharmacology*
  • Indoles/pharmacology*
  • Muscle Development*
  • Muscle, Skeletal/drug effects*
  • Muscle, Skeletal/enzymology
  • Muscle, Skeletal/pathology
  • Muscular Dystrophy, Duchenne/drug therapy*
  • Muscular Dystrophy, Duchenne/enzymology
  • Muscular Dystrophy, Duchenne/genetics
  • Muscular Dystrophy, Duchenne/pathology
  • Protein Processing, Post-Translational
  • Repressor Proteins/antagonists & inhibitors*
  • Repressor Proteins/genetics
  • Repressor Proteins/metabolism
  • Signal Transduction
  • Zebrafish
  • Zebrafish Proteins/antagonists & inhibitors*
  • Zebrafish Proteins/genetics
  • Zebrafish Proteins/metabolism
PubMed
34214631 Full text @ Pharmacol. Res.
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 support its specific inhibition as a new valuable therapeutic approach in the treatment of this pathology.
Genes / Markers
Figures
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Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Antibodies
Orthology
Engineered Foreign Genes
Mapping