Histone Deacetylases: Molecular Mechanisms and Therapeutic Implications for Muscular Dystrophies

Abstract

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.

Keywords: Duchenne Muscular Dystrophy; clinical trials; histone deacetylase; muscular dystrophies.

Figure 1

Histone deacetylase functions in muscle dystrophy condition. The cellular responses that promote MD progression are indicated in red, while in green those that counteract MD pathological features. AChR: acetylcholine receptor; Ac: acetyl group; Fst: follistatin; Mstn: myostatin; Utrn: utrophin; HDAC: histone deacetylase; SIRT: sirtuin; DYSF: Dysferlin; PGC-1α: peroxisome proliferator-activated receptor, gamma, coactivator 1 alpha; TGF-β: transforming growth factor beta.

Figure 2

In vitro evidence of inhibiting HDACs on myoblast or FAP lineage progression. TSA: Trichostatin A; VPA: Valproic acid; PhB: Sodium Butyrate; Fst: follistatin; SCs: satellite cells; FAPs: Fibroadipogenic progenitors.

Figure 3

Use of HDACi in preclinical studies in DMD. Fst: follistatin; Utrn: utrophin; SIRT1: sirtuin 1; OS: oxidative stress; TSA: Trichostatin A; SAHA: suberoylanilide hydroxamic acid.