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 language | English |
|---|---|
| Pages (from-to) | 3010-3023 |
| Number of pages | 14 |
| Journal | Cell Reports |
| Volume | 17 |
| Issue number | 11 |
| DOIs | |
| Publication status | Published - Dec 13 2016 |
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Keywords
- fatty acid oxidation
- histone acetylation
- mitochondrial biogenesis
- muscular dystrophy
ASJC Scopus subject areas
- Biochemistry, Genetics and Molecular Biology(all)
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, Silvia; Cervia, Davide; Di Renzo, Ilaria; Moscheni, Claudia; Ripolone, Michela; Violano, Raffaella; Moggio, Maurizio; Bassi, Maria Teresa; Puri, Pier Lorenzo; Latella, Lucia; Clementi, Emilio Giuseppe Ignazio; De Palma, Clara.
In: Cell Reports, Vol. 17, No. 11, 13.12.2016, p. 3010-3023.Research output: Contribution to journal › Article
}
TY - JOUR
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, Silvia
AU - Cervia, Davide
AU - Di Renzo, Ilaria
AU - Moscheni, Claudia
AU - Ripolone, Michela
AU - Violano, Raffaella
AU - Moggio, Maurizio
AU - Bassi, Maria Teresa
AU - Puri, Pier Lorenzo
AU - Latella, Lucia
AU - Clementi, Emilio Giuseppe Ignazio
AU - De Palma, Clara
PY - 2016/12/13
Y1 - 2016/12/13
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.
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.
KW - fatty acid oxidation
KW - histone acetylation
KW - mitochondrial biogenesis
KW - muscular dystrophy
UR - http://www.scopus.com/inward/record.url?scp=85004043418&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85004043418&partnerID=8YFLogxK
U2 - 10.1016/j.celrep.2016.11.044
DO - 10.1016/j.celrep.2016.11.044
M3 - Article
VL - 17
SP - 3010
EP - 3023
JO - Cell Reports
JF - Cell Reports
SN - 2211-1247
IS - 11
ER -