Givinostat as metabolic enhancer reverting mitochondrial biogenesis deficit in Duchenne Muscular Dystrophy

Matteo Giovarelli, Silvia Zecchini, Giorgia Catarinella, Claudia Moscheni, Patrizia Sartori, Cecilia Barbieri, Paulina Roux-Biejat, Alessandra Napoli, Chiara Vantaggiato, Davide Cervia, Cristiana Perrotta, Emilio Clementi, Lucia Latella, Clara De Palma

Research output: Contribution to journalArticlepeer-review

Abstract

Duchenne Muscular Dystrophy (DMD) is a rare disorder characterized by progressive muscle wasting, weakness, and premature death. Remarkable progress has been made in genetic approaches, restoring dystrophin, or its function. However, the targeting of secondary pathological mechanisms, such as increasing muscle blood flow or stopping fibrosis, remains important to improve the therapeutic benefits, that depend on tackling both the genetic disease and the downstream consequences. Mitochondrial dysfunctions are one of the earliest deficits in DMD, arise from multiple cellular stressors and result in less than 50% of ATP content in dystrophic muscles. Here we establish that there are two temporally distinct phases of mitochondrial damage with depletion of mitochondrial mass at early stages and an accumulation of dysfunctional mitochondria at later stages, leading to a different oxidative fibers pattern, in young and adult mdx mice. We also observe a progressive mitochondrial biogenesis impairment associated with increased deacetylation of peroxisome proliferator-activated receptor-gamma coactivator 1 α (PGC-1α) promoter. Such histone deacetylation is inhibited by givinostat that positively modifies the epigenetic profile of PGC-1α promoter, sustaining mitochondrial biogenesis and oxidative fiber type switch. We, therefore, demonstrate that givinostat exerts relevant effects at mitochondrial level, acting as a metabolic remodeling agent capable of efficiently promoting mitochondrial biogenesis in dystrophic muscle.

Original languageEnglish
Article number105751
JournalPharmacological Research
Volume170
DOIs
Publication statusPublished - Aug 2021

Keywords

  • Duchenne Muscular Dystrophy
  • Givinostat
  • Givinostat (PubChem CID: 9804991)
  • Metabolic agent
  • Mitochondrial biogenesis
  • Oxidative metabolism
  • Trichostatin A (PubChem CID: 444732)

ASJC Scopus subject areas

  • Pharmacology

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