Role of plasminogen activator inhibitor-1 in glucocorticoid-induced muscle change in mice.
Role of plasminogen activator inhibitor-1 in glucocorticoid-induced muscle change in mice.
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纤溶酶原激活剂抑制剂-1 在糖皮质激素诱导的小鼠肌肉变化中的作用。
DOI：
10.1007/s00774-017-0825-8
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发表时间：
2017
影响因子：
3.3
通讯作者：
Kaji H.
中科院分区：
文献类型：
--
作者：
Tamura Y;Kawao N;Shimoide T;Okada K;Matsuo O;Kaji H.
我们最近发现纤溶酶原激活物抑制物-1(PAI-1)是一种丝氨酸蛋白酶抑制物，与糖皮质激素(GC)引起的小鼠糖尿病、骨质疏松症和肌肉萎缩有关。在本研究中，我们在体内和体外研究了GC通过PAI-1诱导肌肉萎缩的详细机制。PAI-1缺乏抑制了阿托品1和肌肉环指蛋白1(MuRF1)的mRNA水平，这是导致肌肉退化的泛素连接酶，而GC处理后这两种基因的表达水平升高。体外研究表明，活性PAI-1处理可增强地塞米松(Dex)对小鼠成肌细胞C2C12的内分泌激素1mRNA水平的上调作用。此外，siRNA降低内源性PAI-1水平可抑制地塞米松增强的C2C12细胞内阿托品1和MuRF1的mRNA水平。相反，内源性PAI-1水平和活性PAI-1的降低并不影响Akt和p70S6激酶的磷酸化，也不影响地塞米松或不加地塞米松的C2C12细胞的成肌分化。此外，PAI-1缺乏抑制了GC处理后小鼠腓肠肌IGF-1mRNA水平的下降，但在地塞米松存在下，活性PAI-1和内源性PAI-1水平的降低都不影响C2C12细胞的IGF-1mRNA水平。综上所述，我们的数据表明，旁分泌PAI-1通过促进小鼠肌肉的降解参与了GC诱导的肌肉萎缩。
We recently revealed that plasminogen activator inhibitor-1 (PAI-1), a serine protease inhibitor, is involved in diabetes, osteoporosis and muscle wasting induced by glucocorticoid (GC) treatment in mice. In the present study, we investigated the detailed mechanisms by which GC induces muscle wasting through PAI-1 in vivo and in vitro. PAI-1 deficiency suppressed the mRNA levels ofatrogin1andmuscle RING-Finger Protein 1(MuRF1), ubiquitin ligases leading to muscle degradation, elevated by GC treatment in the gastrocnemius muscle of mice. In vitro study revealed that active PAI-1 treatment augmented the increase inatrogin1mRNA levels enhanced by dexamethasone (Dex) in mouse myoblastic C2C12 cells. Moreover, a reduction in endogenous PAI-1 level by siRNA suppressed the mRNA levels ofatrogin1andMuRF1enhanced by Dex in C2C12 cells. In contrast, a reduction in endogenous PAI-1 levels and active PAI-1 did not affect the phosphorylations of Akt and p70S6 kinase nor myogenic differentiation with or without Dex in C2C12 cells. In addition, PAI-1 deficiency bluntedIGF-1 mRNA levelsdecreased by GC treatment in the gastrocnemius muscle of mice, although neither active PAI-1 nor a reduction in endogenous PAI-1 levels affected the levels ofIGF-1mRNA in C2C12 cells in the presence of Dex. In conclusion, our data suggest that paracrine PAI-1 is involved in GC-induced muscle wasting through the enhancement of muscle degradation in mice.