HDAC4 Controls Muscle Homeostasis through Deacetylation of Myosin Heavy Chain, PGC-1α, and Hsc70.
Cell Rep
; 29(3): 749-763.e12, 2019 10 15.
Article
em En
| MEDLINE
| ID: mdl-31618641
ABSTRACT
HDAC4, a class IIa histone deacetylase, is upregulated in skeletal muscle in response to denervation-induced atrophy. When HDAC4 is deleted postnatally, mice are partially protected from denervation. Despite the name "histone" deacetylase, HDAC4 demonstrably deacetylates cytosolic and non-histone nuclear proteins. We developed potent and selective class IIa HDAC inhibitors. Using these tools and genetic knockdown, we identified three previously unidentified substrates of HDAC4 myosin heavy chain, peroxisome proliferator-activated receptor gamma co-activator 1alpha (PGC-1α), and heat shock cognate 71 kDa protein (Hsc70). HDAC4 inhibition almost completely prevented denervation-induced loss of myosin heavy chain isoforms and blocked the action of their E3 ligase, MuRF1. PGC-1α directly interacts with class IIa HDACs; selective inhibitors increased PGC-1α protein in muscles. Hsc70 deacetylation by HDAC4 affects its chaperone activity. Through these endogenous HDAC4 substrates, we identified several muscle metabolic pathways that are regulated by class IIa HDACs, opening up new therapeutic options to treat skeletal muscle disorders and potentially other disease where these specific pathways are affected.
Palavras-chave
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Músculo Esquelético
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Cadeias Pesadas de Miosina
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Proteínas de Choque Térmico HSC70
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Coativador 1-alfa do Receptor gama Ativado por Proliferador de Peroxissomo
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Histona Desacetilases
Limite:
Animals
Idioma:
En
Revista:
Cell Rep
Ano de publicação:
2019
Tipo de documento:
Article
País de afiliação:
Estados Unidos