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Histone Deacetylases: Molecular Mechanisms and Therapeutic Implications for Muscular Dystrophies

Histone deacetylases (HDACs) are enzymes that regulate the deacetylation of numerous histone and non-histone proteins, thereby affecting a wide range of cellular processes. Deregulation of HDAC expression or activity is often associated with several pathologies, suggesting potential for targeting th...

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Autores principales: Sandonà, Martina, Cavioli, Giorgia, Renzini, Alessandra, Cedola, Alessia, Gigli, Giuseppe, Coletti, Dario, McKinsey, Timothy A., Moresi, Viviana, Saccone, Valentina
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10002075/
https://www.ncbi.nlm.nih.gov/pubmed/36901738
http://dx.doi.org/10.3390/ijms24054306
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author Sandonà, Martina
Cavioli, Giorgia
Renzini, Alessandra
Cedola, Alessia
Gigli, Giuseppe
Coletti, Dario
McKinsey, Timothy A.
Moresi, Viviana
Saccone, Valentina
author_facet Sandonà, Martina
Cavioli, Giorgia
Renzini, Alessandra
Cedola, Alessia
Gigli, Giuseppe
Coletti, Dario
McKinsey, Timothy A.
Moresi, Viviana
Saccone, Valentina
author_sort Sandonà, Martina
collection PubMed
description Histone deacetylases (HDACs) are enzymes that regulate the deacetylation of numerous histone and non-histone proteins, thereby affecting a wide range of cellular processes. Deregulation of HDAC expression or activity is often associated with several pathologies, suggesting potential for targeting these enzymes for therapeutic purposes. For example, HDAC expression and activity are higher in dystrophic skeletal muscles. General pharmacological blockade of HDACs, by means of pan-HDAC inhibitors (HDACi), ameliorates both muscle histological abnormalities and function in preclinical studies. A phase II clinical trial of the pan-HDACi givinostat revealed partial histological improvement and functional recovery of Duchenne Muscular Dystrophy (DMD) muscles; results of an ongoing phase III clinical trial that is assessing the long-term safety and efficacy of givinostat in DMD patients are pending. Here we review the current knowledge about the HDAC functions in distinct cell types in skeletal muscle, identified by genetic and -omic approaches. We describe the signaling events that are affected by HDACs and contribute to muscular dystrophy pathogenesis by altering muscle regeneration and/or repair processes. Reviewing recent insights into HDAC cellular functions in dystrophic muscles provides new perspectives for the development of more effective therapeutic approaches based on drugs that target these critical enzymes.
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spelling pubmed-100020752023-03-11 Histone Deacetylases: Molecular Mechanisms and Therapeutic Implications for Muscular Dystrophies Sandonà, Martina Cavioli, Giorgia Renzini, Alessandra Cedola, Alessia Gigli, Giuseppe Coletti, Dario McKinsey, Timothy A. Moresi, Viviana Saccone, Valentina Int J Mol Sci Review Histone deacetylases (HDACs) are enzymes that regulate the deacetylation of numerous histone and non-histone proteins, thereby affecting a wide range of cellular processes. Deregulation of HDAC expression or activity is often associated with several pathologies, suggesting potential for targeting these enzymes for therapeutic purposes. For example, HDAC expression and activity are higher in dystrophic skeletal muscles. General pharmacological blockade of HDACs, by means of pan-HDAC inhibitors (HDACi), ameliorates both muscle histological abnormalities and function in preclinical studies. A phase II clinical trial of the pan-HDACi givinostat revealed partial histological improvement and functional recovery of Duchenne Muscular Dystrophy (DMD) muscles; results of an ongoing phase III clinical trial that is assessing the long-term safety and efficacy of givinostat in DMD patients are pending. Here we review the current knowledge about the HDAC functions in distinct cell types in skeletal muscle, identified by genetic and -omic approaches. We describe the signaling events that are affected by HDACs and contribute to muscular dystrophy pathogenesis by altering muscle regeneration and/or repair processes. Reviewing recent insights into HDAC cellular functions in dystrophic muscles provides new perspectives for the development of more effective therapeutic approaches based on drugs that target these critical enzymes. MDPI 2023-02-21 /pmc/articles/PMC10002075/ /pubmed/36901738 http://dx.doi.org/10.3390/ijms24054306 Text en © 2023 by the authors. https://creativecommons.org/licenses/by/4.0/Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).
spellingShingle Review
Sandonà, Martina
Cavioli, Giorgia
Renzini, Alessandra
Cedola, Alessia
Gigli, Giuseppe
Coletti, Dario
McKinsey, Timothy A.
Moresi, Viviana
Saccone, Valentina
Histone Deacetylases: Molecular Mechanisms and Therapeutic Implications for Muscular Dystrophies
title Histone Deacetylases: Molecular Mechanisms and Therapeutic Implications for Muscular Dystrophies
title_full Histone Deacetylases: Molecular Mechanisms and Therapeutic Implications for Muscular Dystrophies
title_fullStr Histone Deacetylases: Molecular Mechanisms and Therapeutic Implications for Muscular Dystrophies
title_full_unstemmed Histone Deacetylases: Molecular Mechanisms and Therapeutic Implications for Muscular Dystrophies
title_short Histone Deacetylases: Molecular Mechanisms and Therapeutic Implications for Muscular Dystrophies
title_sort histone deacetylases: molecular mechanisms and therapeutic implications for muscular dystrophies
topic Review
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10002075/
https://www.ncbi.nlm.nih.gov/pubmed/36901738
http://dx.doi.org/10.3390/ijms24054306
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