Reversal of Defective Mitochondrial Biogenesis in Limb-Girdle Muscular Dystrophy 2D by Independent Modulation of Histone and PGC-1α Acetylation

Sarah Pambianco, Matteo Giovarelli, C. Perrotta, Silvia Zecchini, Davide Cervia, Ilaria Di Renzo, Claudia Moscheni, Michela Ripolone, Raffaella Violano, Maurizio Moggio, Maria Teresa Bassi, Pier Lorenzo Puri, Lucia Latella, Emilio Giuseppe Ignazio Clementi, Clara De Palma

Research output: Contribution to journalArticlepeer-review

Abstract

Mitochondrial dysfunction occurs in many muscle degenerative disorders. Here, we demonstrate that mitochondrial biogenesis was impaired in limb-girdle muscular dystrophy (LGMD) 2D patients and mice and was associated with impaired OxPhos capacity. Two distinct approaches that modulated histones or peroxisome proliferator-activated receptor-gamma coactivator 1 α (PGC-1α) acetylation exerted equivalent functional effects by targeting different mitochondrial pathways (mitochondrial biogenesis or fatty acid oxidation[FAO]). The histone deacetylase inhibitor Trichostatin A (TSA) changed chromatin assembly at the PGC-1α promoter, restored mitochondrial biogenesis, and enhanced muscle oxidative capacity. Conversely, nitric oxide (NO) triggered post translation modifications of PGC-1α and induced FAO, recovering the bioenergetics impairment of muscles but shunting the defective mitochondrial biogenesis. In conclusion, a transcriptional blockade of mitochondrial biogenesis occurred in LGMD-2D and could be recovered by TSA changing chromatin conformation, or it could be overcome by NO activating a mitochondrial salvage pathway.

Original languageEnglish
Pages (from-to)3010-3023
Number of pages14
JournalCell Reports
Volume17
Issue number11
DOIs
Publication statusPublished - Dec 13 2016

Keywords

  • fatty acid oxidation
  • histone acetylation
  • mitochondrial biogenesis
  • muscular dystrophy

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

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