title: Reversal of Defective Mitochondrial Biogenesis in Limb-Girdle Muscular Dystrophy 2D by Independent Modulation of Histone and PGC-1α Acetylation.
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.
authors.affiliation: Department of Biomedical and Clinical Sciences "Luigi Sacco," Università degli Studi di Milano, 20157 Milano, Italy.
authors.forename: Sarah
authors.initials: S
authors.lastname: Pambianco
authors.affiliation: Department of Biomedical and Clinical Sciences "Luigi Sacco," Università degli Studi di Milano, 20157 Milano, Italy.
authors.forename: Matteo
authors.initials: M
authors.lastname: Giovarelli
authors.affiliation: Department of Biomedical and Clinical Sciences "Luigi Sacco," Università degli Studi di Milano, 20157 Milano, Italy.
authors.forename: Cristiana
authors.initials: C
authors.lastname: Perrotta
authors.affiliation: Department of Biomedical and Clinical Sciences, Unit of Clinical Pharmacology, University Hospital "Luigi Sacco"-ASST Fatebenefratelli Sacco, National Research Council-Institute of Neuroscience, Università degli Studi di Milano, 20157 Milano, Italy.
authors.forename: Silvia
authors.initials: S
authors.lastname: Zecchini
authors.affiliation: Department of Biomedical and Clinical Sciences "Luigi Sacco," Università degli Studi di Milano, 20157 Milano, Italy; Department for Innovation in Biological, Agro-food and Forest systems, Università degli Studi della Tuscia, 01100 Viterbo, Italy.
authors.forename: Davide
authors.initials: D
authors.lastname: Cervia
authors.affiliation: Department of Biomedical and Clinical Sciences "Luigi Sacco," Università degli Studi di Milano, 20157 Milano, Italy.
authors.forename: Ilaria
authors.initials: I
authors.lastname: Di Renzo
authors.affiliation: Department of Biomedical and Clinical Sciences "Luigi Sacco," Università degli Studi di Milano, 20157 Milano, Italy.
authors.forename: Claudia
authors.initials: C
authors.lastname: Moscheni
authors.affiliation: Neuromuscular Unit, Dino Ferrari Centre, IRCCS Foundation Ca' Granda Ospedale Maggiore Policlinico, Università degli Studi di Milano, 20122 Milano, Italy.
authors.forename: Michela
authors.initials: M
authors.lastname: Ripolone
authors.affiliation: Neuromuscular Unit, Dino Ferrari Centre, IRCCS Foundation Ca' Granda Ospedale Maggiore Policlinico, Università degli Studi di Milano, 20122 Milano, Italy.
authors.forename: Raffaella
authors.initials: R
authors.lastname: Violano
authors.affiliation: Neuromuscular Unit, Dino Ferrari Centre, IRCCS Foundation Ca' Granda Ospedale Maggiore Policlinico, Università degli Studi di Milano, 20122 Milano, Italy.
authors.forename: Maurizio
authors.initials: M
authors.lastname: Moggio
authors.affiliation: IRCCS Eugenio Medea, 23842 Bosisio Parini, Italy.
authors.forename: Maria Teresa
authors.initials: MT
authors.lastname: Bassi
authors.affiliation: Epigenetics and Regenerative Pharmacology, IRCCS Fondazione Santa Lucia, 00142 Roma, Italy; Sanford Children's Health Research Center, Sanford Prebys Burnham Medical Discovery Institute, La Jolla, CA 92037, USA.
authors.forename: Pier Lorenzo
authors.initials: PL
authors.lastname: Puri
authors.affiliation: Epigenetics and Regenerative Pharmacology, IRCCS Fondazione Santa Lucia, 00142 Roma, Italy; National Research Council-Institute of Translational Pharmacology, 00179 Roma, Italy.
authors.forename: Lucia
authors.initials: L
authors.lastname: Latella
authors.affiliation: Department of Biomedical and Clinical Sciences, Unit of Clinical Pharmacology, University Hospital "Luigi Sacco"-ASST Fatebenefratelli Sacco, National Research Council-Institute of Neuroscience, Università degli Studi di Milano, 20157 Milano, Italy; IRCCS Eugenio Medea, 23842 Bosisio Parini, Italy. Electronic address: emilio.clementi@unimi.it.
authors.forename: Emilio
authors.initials: E
authors.lastname: Clementi
authors.affiliation: Department of Biomedical and Clinical Sciences, Unit of Clinical Pharmacology, University Hospital "Luigi Sacco"-ASST Fatebenefratelli Sacco, National Research Council-Institute of Neuroscience, Università degli Studi di Milano, 20157 Milano, Italy. Electronic address: clara.depalma@unimi.it.
authors.forename: Clara
authors.initials: C
authors.lastname: De Palma
mesh_terms: D000107:Acetylation; D000818:Animals; D002843:Chromatin / Q000235:genetics / Q000378:metabolism; D005227:Fatty Acids / Q000378:metabolism*; D006657:Histones / Q000235:genetics / Q000378:metabolism; D006801:Humans; D050356:Lipid Metabolism / Q000235:genetics; D051379:Mice; D008928:Mitochondria / Q000235:genetics* / Q000473:pathology; D049288:Muscular Dystrophies, Limb-Girdle / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D009569:Nitric Oxide / Q000378:metabolism; D001678:Organelle Biogenesis; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha / Q000235:genetics / Q000378:metabolism; D011499:Protein Processing, Post-Translational / Q000235:genetics*
chemical_list: D002843:Chromatin; D005227:Fatty Acids; D006657:Histones; C486497:PPARGC1A protein, human; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; D009569:Nitric Oxide
keywords: fatty acid oxidation; histone acetylation; mitochondrial biogenesis; muscular dystrophy