Preclinical Studies in the mdx Mouse Model of Duchenne Muscular Dystrophy with the Histone Deacetylase Inhibitor Givinostat

Abstract

Previous work has established the existence of dystrophin-nitric oxide (NO) signaling to histone deacetylases (HDACs) that is deregulated in dystrophic muscles. As such, pharmacological interventions that target HDACs (that is, HDAC inhibitors) are of potential therapeutic interest for the treatment of muscular dystrophies. In this study, we explored the effectiveness of long-term treatment with different doses of the HDAC inhibitor givinostat in mdx mice-the mouse model of Duchenne muscular dystrophy (DMD). This study identified an efficacy for recovering functional and histological parameters within a window between 5 and 10 mg/kg/d of givinostat, with evident reduction of the beneficial effects with 1 mg/kg/d dosage. The long-term (3.5 months) exposure of 1.5-month-old mdx mice to optimal concentrations of givinostat promoted the formation of muscles with increased cross-sectional area and reduced fibrotic scars and fatty infiltration, leading to an overall improvement of endurance performance in treadmill tests and increased membrane stability. Interestingly, a reduced inflammatory infiltrate was observed in muscles of mdx mice exposed to 5 and 10 mg/kg/d of givinostat. A parallel pharmacokinetic/pharmacodynamic analysis confirmed the relationship between the effective doses of givinostat and the drug distribution in muscles and blood of treated mice. These findings provide the preclinical basis for an immediate translation of givinostat into clinical studies with DMD patients.

The histone deacetylase inhibitor butyrate improves metabolism and reduces muscle atrophy during aging

“…In fact, pharmacological inhibitors of HDACs have also shown promise in preclinical models of diseases of muscle, including amyotrophic lateral sclerosis (Yoo & Ko, 2011), spinal muscular atrophy (Minamiyama et al ., 2004) and muscular dystrophy (Consalvi et al ., 2013). For example, HDAC inhibitors reduce fibrosis and improve muscle function in a mouse model of muscular dystrophy (Consalvi et al ., 2013).…”

“…For example, HDAC inhibitors reduce fibrosis and improve muscle function in a mouse model of muscular dystrophy (Consalvi et al ., 2013). Because pharmacological inhibitors of class I and II HDACs have been shown to ameliorate neuromuscular disease in animal models, we asked whether the general HDAC inhibitor butyrate could attenuate muscle atrophy and improve metabolism during aging.…”

New insights into the epigenetic control of satellite cells

“…In amyotrophic lateral sclerosis, HDAC inhibitors have been proposed as potential drugs to ameliorate patient symptoms [104,105] . In the case of muscular dystrophy, HDAC inhibitors have been extensively studied using the mdx mouse model [106] ; currently, these drugs are under review in a clinical trial for muscular dystrophy [107] . Their effects are believed to be primarily due to the inhibition of class Ⅰ HDACs [108] .…”

HDAC inhibitors for muscular dystrophies: progress and prospects

“…[10,11] In principle, the rationale for the use of HDACi in the treatment of DMD was provided by the finding that dystrophin-deficient muscles display an aberrant, constitutive activation of HDAC2, as a consequence of reduced nitric oxide (NO)-mediated NO-dependent S-nitrosylation in myofibers. [12] Moreover, recent studies have revealed complex epigenetic networks targeted by HDACi in MuSCs and FAPs.…”

“…Studies with HDACi in mdx mice demonstrated that the morphological recovery is accompanied by increased muscle strength and exercise performance. [10,11] Thus, matching functional tests, such as 6 Minute Walk Test (6MWT) and North Star Ambulatory Assessment, with the histological evaluation of treated muscles, will be mandatory to reveal the efficacy of HDACi and other pharmacological interventions in DMD patients.…”