Giovarelli 2021 Pharmacol Res

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Giovarelli M, Zecchini S, Catarinella G, Moscheni C, Sartori P, Barbieri C, Roux-Biejat P, Napoli A, Vantaggiato C, Cervia D, Perrotta C, Clementi E, Latella L, De Palma C (2021) Givinostat as metabolic enhancer reverting mitochondrial biogenesis deficit in Duchenne Muscular Dystrophy. Pharmacol Res 170:105751.

Β» PMID: 34197911 Open Access

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 (2021) Pharmacol Res

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 Ξ± (PGC-1Ξ±) promoter. Such histone deacetylation is inhibited by givinostat that positively modifies the epigenetic profile of PGC-1Ξ± 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. β€’ Keywords: Duchenne muscular dystrophy, Givinostat, Givinostat (PubChem CID: 9804991), Metabolic agent, Mitochondrial biogenesis, Oxidative metabolism, Trichostatin A (PubChem CID: 444732) β€’ Bioblast editor: Reiswig R β€’ O2k-Network Lab: IT Milan Clementi E

Labels: MiParea: Respiration, mt-Biogenesis;mt-density, Pharmacology;toxicology  Pathology: Other 

Organism: Mouse  Tissue;cell: Skeletal muscle  Preparation: Permeabilized tissue 

Coupling state: LEAK, OXPHOS  Pathway: N, S, CIV, NS, ROX  HRR: Oxygraph-2k 


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