Utilizza questo identificativo per citare o creare un link a questo documento: http://hdl.handle.net/2067/43542
Titolo: Givinostat as metabolic enhancer reverting mitochondrial biogenesis deficit in Duchenne Muscular Dystrophy
Autori: Giovarelli, Matteo
Zecchini, Silvia
Catarinella, Giorgia
Moscheni, Claudia
Sartori, Patrizia
Barbieri, Cecilia
Roux-Biejat, Paulina
Napoli, Alessandra
Vantaggiato, Chiara
Cervia, Davide 
Perrotta, Cristiana
Clementi, Emilio
Latella, Lucia
De Palma, Clara
Data pubblicazione: 2021
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 results 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.
URI: http://hdl.handle.net/2067/43542
ISSN: 1043-6618
DOI: 10.1016/j.phrs.2021.105751
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