HDAC4 Knockdown Alleviates Denervation-Induced Muscle Atrophy by Inhibiting Myogenin-Dependent Atrogene Activation.
HDAC4 Knockdown Alleviates Denervation-Induced Muscle Atrophy by Inhibiting Myogenin-Dependent Atrogene Activation.
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HDAC4 敲低通过抑制肌细胞生成素依赖性 Atrogene 激活减轻去神经诱导的肌肉萎缩
DOI：
10.3389/fncel.2021.663384
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发表时间：
2021
影响因子：
5.3
通讯作者：
Sun H
中科院分区：
文献类型：
--
作者：
Ma W;Cai Y;Shen Y;Chen X;Zhang L;Ji Y;Chen Z;Zhu J;Yang X;Sun H
失神经支配可激活骨骼肌的分解代谢途径，导致进行性骨骼肌萎缩。目前，对于肌肉萎缩还没有有效的治疗方法。组蛋白去乙酰化酶4（HDAC 4）与肌肉萎缩密切相关，但其在失神经诱导的肌肉萎缩中的作用机制尚不清楚。在这项研究中，我们发现HDAC 4在失神经骨骼肌中的表达显著增加。HDAC 4抑制可有效减轻失神经诱导的肌萎缩，降低肌肉特异性E3泛素连接酶（MuRF 1和MAFbx）和自噬相关蛋白（Atg 7、LC 3B、PINK 1和BNIP 3）的表达，抑制I型肌纤维向II型肌纤维的转化，增强SIRT 1和PGC-1 α的表达。转录组测序和生物信息学分析表明，HDAC 4可能通过调节肌肉适应、细胞分裂、细胞周期、凋亡过程、骨骼肌萎缩和细胞分化等对去神经支配的反应而参与去神经诱导的肌肉萎缩。STRING分析表明HDAC 4可能通过直接调节肌细胞生成素（MYOG）、细胞周期抑制因子p21（CDKN 1A）和盐诱导激酶1（SIK 1）参与肌萎缩过程。失神经骨骼肌MYOG显著增加，抑制MYOG可显著减轻失神经骨骼肌萎缩，同时伴有MuRF 1和MAFbx的降低。MYOG过表达可降低HDAC 4抑制对失神经诱导的肌肉萎缩的保护作用，如肌肉质量和肌纤维横截面积的减少以及线粒体自噬的增加所证明的。综上所述，HDAC 4抑制剂可通过降低MYOG表达来减轻去神经诱导的肌肉萎缩，HDAC 4还与骨骼肌中的CDKN 1A和SIK 1直接相关，这表明HDAC 4抑制剂可能是治疗神经源性肌肉萎缩的潜在药物。这些结果不仅丰富了去神经诱导肌肉萎缩的分子调控机制，也为HDAC 4-MYOG轴作为预防和治疗肌肉萎缩的新靶点提供了实验依据。
Denervation can activate the catabolic pathway in skeletal muscle and lead to progressive skeletal muscle atrophy. At present, there is no effective treatment for muscle atrophy. Histone deacetylase 4 (HDAC4) has recently been found to be closely related to muscle atrophy, but the underlying mechanism of HDAC4 in denervation-induced muscle atrophy have not been described clearly yet. In this study, we found that the expression of HDAC4 increased significantly in denervated skeletal muscle. HDAC4 inhibition can effectively diminish denervation-induced muscle atrophy, reduce the expression of muscle specific E3 ubiquitin ligase (MuRF1 and MAFbx) and autophagy related proteins (Atg7, LC3B, PINK1 and BNIP3), inhibit the transformation of type I fibers to type II fibers, and enhance the expression of SIRT1 and PGC-1 α. Transcriptome sequencing and bioinformatics analysis was performed and suggested that HDAC4 may be involved in denervation-induced muscle atrophy by regulating the response to denervation involved in the regulation of muscle adaptation, cell division, cell cycle, apoptotic process, skeletal muscle atrophy, and cell differentiation. STRING analysis showed that HDAC4 may be involved in the process of muscle atrophy by directly regulating myogenin (MYOG), cell cycle inhibitor p21 (CDKN1A) and salt induced kinase 1 (SIK1). MYOG was significantly increased in denervated skeletal muscle, and MYOG inhibition could significantly alleviate denervation-induced muscle atrophy, accompanied by the decreased MuRF1 and MAFbx. MYOG overexpression could reduce the protective effect of HDAC4 inhibition on denervation-induced muscle atrophy, as evidenced by the decreased muscle mass and cross-sectional area of muscle fibers, and the increased mitophagy. Taken together, HDAC4 inhibition can alleviate denervation-induced muscle atrophy by reducing MYOG expression, and HDAC4 is also directly related to CDKN1A and SIK1 in skeletal muscle, which suggests that HDAC4 inhibitors may be a potential drug for the treatment of neurogenic muscle atrophy. These results not only enrich the molecular regulation mechanism of denervation-induced muscle atrophy, but also provide the experimental basis for HDAC4-MYOG axis as a new target for the prevention and treatment of muscular atrophy.
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影响因子：
2.4
作者：
Berti F;Nogueira JM;Wöhrle S;Sobreira DR;Hawrot K;Dietrich S
通讯作者：
Dietrich S
DOI：
10.12659/msm.897909
发表时间：
2016-04-07
期刊：
Medical science monitor : international medical journal of experimental and clinical research
影响因子：
--
作者：
Huang QK;Qiao HY;Fu MH;Li G;Li WB;Chen Z;Wei J;Liang BS
通讯作者：
Liang BS
影响因子：
7.7
作者：
Choi, Moon-Chang;Ryu, Soyoung;Yao, Tso-Pang
通讯作者：
Yao, Tso-Pang
DOI：
10.4161/trns.20914
发表时间：
2012-09
期刊：
Transcription
影响因子：
--
作者：
Bharathy N;Taneja R
通讯作者：
Taneja R
影响因子：
4.5
作者：
Chalkiadaki A;Igarashi M;Nasamu AS;Knezevic J;Guarente L
通讯作者：
Guarente L