While class IIa HDACs play redundant roles in the establishment of the metabolic pattern of skeletal muscle fibers, by repressing MEF2, HDAC4 per se is necessary and sufficient to mediate responses upon different stimuli in skeletal muscle. Despite binding and repressing the activity of two major myogenic factors, i.e., MEF2 and SRF, mice harboring a skeletal-muscle specific deletion of Hdac4 are viable and do not display obvious defects in skeletal muscle. Increased expression of HDAC4 has been detected in skeletal muscle in different diseases, such as Duchenne Muscular Dystrophy (DMD) and Amyotrophic Lateral Sclerosis (ALS) : importantly, the observations in pre-clinical models have been validated in patients. In addition, HDACs deacetylate non-histone proteins, such as p53 as one of the first identified HDAC targets, thus regulating their activity.Īmong the members of class IIa, HDAC4 plays crucial functions in striated muscles. Therefore, the balance between the levels of histone deacetylation and acetylation plays a key role in the modulation of gene transcription and governs numerous developmental processes, being involved in the regulation of various genes associated with signal transduction, cell growth, and cell death, as well as disease states, including fluid and electrolyte disorders or cancers. By doing this, HDACs influence the delicate balance between euchromatin and heterochromatin, thereby widely affecting gene expression in a prolonged fashion. The latter is mediated by histone deacetylases (HDACs). Histone acetylation is probably the most well-characterized of these modifications, with hyperacetylation leading to an increase in gene expression, due to the relaxation of chromatin structure, while hypoacetylation has the opposite effect. Transcriptional regulation in eukaryotes is strongly influenced by post-translational modifications (PTMs) of histones, the core proteins of chromatin, such as phosphorylation, methylation, and acetylation. 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. We describe the signaling events that are affected by HDACs and contribute to muscular dystrophy pathogenesis by altering muscle regeneration and/or repair processes. Here we review the current knowledge about the HDAC functions in distinct cell types in skeletal muscle, identified by genetic and -omic approaches. 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. General pharmacological blockade of HDACs, by means of pan-HDAC inhibitors (HDACi), ameliorates both muscle histological abnormalities and function in preclinical studies. For example, HDAC expression and activity are higher in dystrophic skeletal muscles. Deregulation of HDAC expression or activity is often associated with several pathologies, suggesting potential for targeting these enzymes for therapeutic purposes. Histone deacetylases (HDACs) are enzymes that regulate the deacetylation of numerous histone and non-histone proteins, thereby affecting a wide range of cellular processes.
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