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, S. Zecchini, Davide Cervia, Ilaria Di Renzo, Claudia Moscheni, M. Ripolone, R. Violano, M. Moggio, M.T. Bassi, P.L. Puri, L. Latella, E. Clementi, Carla Palma

Research output: Contribution to journalArticle

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. © 2016 The Authors
Original languageEnglish
Pages (from-to)3010-3023
Number of pages14
JournalCell Reports
Volume17
Issue number11
DOIs
Publication statusPublished - 2016

Cite this

Reversal of Defective Mitochondrial Biogenesis in Limb-Girdle Muscular Dystrophy 2D by Independent Modulation of Histone and PGC-1α Acetylation. / Pambianco, Sarah; Giovarelli, Matteo; Perrotta, C.; Zecchini, S.; Cervia, Davide; Di Renzo, Ilaria; Moscheni, Claudia; Ripolone, M.; Violano, R.; Moggio, M.; Bassi, M.T.; Puri, P.L.; Latella, L.; Clementi, E.; Palma, Carla.

In: Cell Reports, Vol. 17, No. 11, 2016, p. 3010-3023.

Research output: Contribution to journalArticle

Pambianco, Sarah ; Giovarelli, Matteo ; Perrotta, C. ; Zecchini, S. ; Cervia, Davide ; Di Renzo, Ilaria ; Moscheni, Claudia ; Ripolone, M. ; Violano, R. ; Moggio, M. ; Bassi, M.T. ; Puri, P.L. ; Latella, L. ; Clementi, E. ; Palma, Carla. / Reversal of Defective Mitochondrial Biogenesis in Limb-Girdle Muscular Dystrophy 2D by Independent Modulation of Histone and PGC-1α Acetylation. In: Cell Reports. 2016 ; Vol. 17, No. 11. pp. 3010-3023.
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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. {\circledC} 2016 The Authors",
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T1 - Reversal of Defective Mitochondrial Biogenesis in Limb-Girdle Muscular Dystrophy 2D by Independent Modulation of Histone and PGC-1α Acetylation

AU - Pambianco, Sarah

AU - Giovarelli, Matteo

AU - Perrotta, C.

AU - Zecchini, S.

AU - Cervia, Davide

AU - Di Renzo, Ilaria

AU - Moscheni, Claudia

AU - Ripolone, M.

AU - Violano, R.

AU - Moggio, M.

AU - Bassi, M.T.

AU - Puri, P.L.

AU - Latella, L.

AU - Clementi, E.

AU - Palma, Carla

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PY - 2016

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N2 - 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. © 2016 The Authors

AB - 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. © 2016 The Authors

KW - fatty acid oxidation

KW - histone acetylation

KW - mitochondrial biogenesis

KW - muscular dystrophy

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