Novartis Institute for Biomedical Research, 181 Massachusetts Avenue, Cambridge, MA 02139, USA.
Novartis Institute for Biomedical Research, 4056 Basel, Switzerland.
Cell Rep. 2019 Oct 15;29(3):749-763.e12. doi: 10.1016/j.celrep.2019.09.023.
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.
HDAC4 是一种 IIa 类组蛋白去乙酰化酶，在骨骼肌中对去神经诱导的萎缩有反应而上调。当 HDAC4 在出生后被删除时，小鼠会部分免受去神经的影响。尽管名字叫“组蛋白”去乙酰化酶，但 HDAC4 明显去乙酰化细胞质和非组蛋白核蛋白。我们开发了强效和选择性的 IIa 类 HDAC 抑制剂。使用这些工具和基因敲低，我们鉴定了 HDAC4 的三个以前未识别的底物：肌球蛋白重链、过氧化物酶体增殖物激活受体γ共激活因子 1α（PGC-1α）和热休克同源 71 kDa 蛋白（Hsc70）。HDAC4 抑制几乎完全阻止了去神经诱导的肌球蛋白重链同工型的丢失，并阻止了其 E3 连接酶 MuRF1 的作用。PGC-1α 与 IIa 类 HDACs 直接相互作用；选择性抑制剂增加了肌肉中的 PGC-1α 蛋白。HDAC4 对 Hsc70 的去乙酰化作用会影响其伴侣活性。通过这些内源性的 HDAC4 底物，我们鉴定了几个受 IIa 类 HDAC 调节的肌肉代谢途径，为治疗骨骼肌疾病和其他可能受这些特定途径影响的疾病开辟了新的治疗选择。
