The nuclear phosphatase SCP4 regulates FoxO transcription factors during muscle wasting in chronic kidney disease.
The nuclear phosphatase SCP4 regulates FoxO transcription factors during muscle wasting in chronic kidney disease.
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DOI：
10.1016/j.kint.2017.02.031
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发表时间：
2017-08
影响因子：
19.6
通讯作者：
Hu Z
中科院分区：
文献类型：
--
作者：
Liu X;Yu R;Sun L;Garibotto G;Lin X;Wang Y;Thomas SS;Li R;Hu Z
慢性肾脏疾病（CKD）和相关的炎症反应会刺激蛋白质能量消耗，这是一种导致肌肉质量损失的并发症。肌肉萎缩主要是通过自噬/溶酶体和蛋白酶体途径加速蛋白质降解引起的，但调节这些蛋白质水解途径的机制尚不清楚。由于FoxOs的去磷酸化调节泛素/蛋白酶体蛋白代谢，我们测试了一种新的核磷酸酶，小c端结构域磷酸酶（SCP） 4，是否调节FoxOs信号传导，进而调节肌肉萎缩。在培养的小鼠成肌细胞中，SCP4过表达刺激蛋白水解，而SCP4敲低则阻止炎症细胞因子刺激的蛋白水解。SCP4过表达导致FoxO1/3a的核积累，随后肌肉生长抑制素、Atrogin-1和MuRF-1等分解代谢因子的表达增加，并诱导溶酶体介导的蛋白水解。用促炎细胞因子治疗C2C12肌管，以NF-κ b依赖的方式刺激SCP4的表达。在CKD小鼠骨骼肌中，SCP4表达上调。同样，在CKD患者的骨骼肌中，SCP4表达显著升高。敲低SCP4可显著抑制fox01 /3a介导的Atrogin-1和MuRF-1的表达，防止CKD小鼠肌肉萎缩。因此，SCP4是FoxO转录因子的新调控因子，可促进细胞蛋白水解。因此，靶向SCP4可能会防止CKD和其他分解代谢疾病的肌肉萎缩。
Chronic kidney disease (CKD) and related inflammatory responses stimulate protein-energy wasting, a complication causing loss of muscle mass. Primarily, muscle wasting results from accelerated protein degradation via autophagic/lysosomal and proteasomal pathways, but mechanisms regulating these proteolysis pathways remain unclear. Since dephosphorylation of FoxOs regulates ubiquitin/proteasome protein metabolism, we tested whether a novel nuclear phosphatase, the small C-terminal domain phosphatase (SCP) 4, regulates FoxOs signaling and, in turn, muscle wasting. In cultured mouse myoblast cells, SCP4 overexpression stimulated proteolysis while knockdown of SCP4 prevented the proteolysis stimulated by inflammatory cytokines. SCP4 overexpression led to nuclear accumulation of FoxO1/3a followed by increased expression of catabolic factors including myostatin, Atrogin-1 and MuRF-1, and induction of lysosomal-mediated proteolysis. Treatment of C2C12 myotubes with proinflammatory cytokines stimulated SCP4 expression in an NF-κB-dependent manner. In skeletal muscle of mice with CKD, SCP4 expression was up-regulated. Similarly, in skeletal muscle of patients with CKD, SCP4 expression was significantly increased. Knockdown of SCP4 significantly suppressed FoxO1/3a-mediated expression of Atrogin-1 and MuRF-1 and prevented muscle wasting in mice with CKD. Thus, SCP4 is a novel regulator of FoxO transcription factors and promotes cellular proteolysis. Hence, targeting SCP4 may prevent muscle wasting in CKD and possibly other catabolic conditions.
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影响因子：
16.6
作者：
Milan, Giulia;Romanello, Vanina;Pescatore, Francesca;Armani, Andrea;Paik, Ji-Hye;Frasson, Laura;Seydel, Anke;Zhao, Jinghui;Abraham, Reimar;Goldberg, Alfred L.;Blaauw, Bert;DePinho, Ronald A.;Sandri, Marco
通讯作者：
Sandri, Marco
影响因子：
4.8
作者：
Doyle, Alexander;Zhang, Guohua;Li, Yi-Ping
通讯作者：
Li, Yi-Ping
CKD 通过 Rho 相关蛋白激酶 1 激活刺激肌肉蛋白损失
影响因子：
13.6
作者：
Peng, Hui;Cao, Jin;Hu, Zhaoyong
通讯作者：
Hu, Zhaoyong
DOI：
10.1097/01.mco.0000165005.01331.45
发表时间：
2005-05-01
影响因子：
3.1
作者：
Franch, HA;Price, SR
通讯作者：
Price, SR
影响因子：
4.8
作者：
Du, J;Mitch, WE;Price, SR
通讯作者：
Price, SR