期刊
CELL REPORTS
卷 17, 期 11, 页码 3010-3023出版社
CELL PRESS
DOI: 10.1016/j.celrep.2016.11.044
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类别
资金
- Telethon network of Genetic biobanks [GTB12001]
- Ministero della Salute Giovani Ricercatori [GR-2011-02350544]
- Ricerca corrente
- Ministero dell'Istruzione, Universita e Ricerca PRIN
- Epigen Project [PB. P01.001.019]
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 alpha (PGC-1 alpha) 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-1 alpha promoter, restored mitochondrial biogenesis, and enhanced muscle oxidative capacity. Conversely, nitric oxide (NO) triggered post translation modifications of PGC-1 alpha 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.
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