IGF-1 prevents ANG II-induced skeletal muscle atrophy via Akt- and Foxo-dependent inhibition of the ubiquitin ligase atrogin-1 expression.
IGF-1 prevents ANG II-induced skeletal muscle atrophy via Akt- and Foxo-dependent inhibition of the ubiquitin ligase atrogin-1 expression.
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DOI：
10.1152/ajpheart.00146.2010
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发表时间：
2010-05
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影响因子：
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通讯作者：
Tadashi Yoshida;L. Semprun-Prieto;S. Sukhanov;P. Delafontaine
中科院分区：
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作者：
Tadashi Yoshida;L. Semprun-Prieto;S. Sukhanov;P. Delafontaine
充血性心力衰竭与肾素-血管紧张素系统的激活和骨骼肌萎缩有关。血管紧张素II(Ang II)可促进肌肉蛋白分解，减少循环和骨骼肌IGF-1。我们以前已经证明，骨骼肌特异性过表达IGF-1可以阻止Ang II诱导的蛋白分解和细胞凋亡。这些发现表明，骨骼肌中IGF-1信号的下调在Ang II的耗竭作用中发挥了重要作用。然而，IGF-1阻止Ang II诱导的骨骼肌萎缩的信号通路和机制尚不清楚。在这里，我们展示了Ang II诱导的两个泛素连接酶Avergin-1和肌肉环指-1(Murf-1)的转录调控，这两个酶的转录调控先于骨骼肌IGF-1的表达，表明激活Avergin-1和MURF-1是导致Ang II反应的骨骼肌萎缩的最初机制。骨骼肌中IGF-1的过表达阻止了Ang II诱导的骨骼肌萎缩和Avergin-1的表达，但不能阻止Murf-1的表达。显性负性Akt和固有活性的FOXO-1阻断了IGF-1阻止Ang II介导的阿托金-1上调和骨骼肌萎缩的能力。我们的发现表明，IGF-1阻止Ang II诱导的骨骼肌萎缩的能力是通过Akt和FOXO-1依赖的信号通路介导的，该信号通路导致阿托金-1而不是Murf-1的表达被抑制。这些数据有力地表明，阿托金-1在血管紧张素II诱导的体内消瘦机制中起着关键作用。
Congestive heart failure is associated with activation of the renin-angiotensin system and skeletal muscle wasting. Angiotensin II (ANG II) has been shown to increase muscle proteolysis and decrease circulating and skeletal muscle IGF-1. We have shown previously that skeletal muscle-specific overexpression of IGF-1 prevents proteolysis and apoptosis induced by ANG II. These findings indicated that downregulation of IGF-1 signaling in skeletal muscle played an important role in the wasting effect of ANG II. However, the signaling pathways and mechanisms whereby IGF-1 prevents ANG II-induced skeletal muscle atrophy are unknown. Here we show ANG II-induced transcriptional regulation of two ubiquitin ligases atrogin-1 and muscle ring finger-1 (MuRF-1) that precedes the reduction of skeletal muscle IGF-1 expression, suggesting that activation of atrogin-1 and MuRF-1 is an initial mechanism leading to skeletal muscle atrophy in response to ANG II. IGF-1 overexpression in skeletal muscle prevented ANG II-induced skeletal muscle wasting and the expression of atrogin-1, but not MuRF-1. Dominant-negative Akt and constitutively active Foxo-1 blocked the ability of IGF-1 to prevent ANG II-mediated upregulation of atrogin-1 and skeletal muscle wasting. Our findings demonstrate that the ability of IGF-1 to prevent ANG II-induced skeletal muscle wasting is mediated via an Akt- and Foxo-1-dependent signaling pathway that results in inhibition of atrogin-1 but not MuRF-1 expression. These data suggest strongly that atrogin-1 plays a critical role in mechanisms of ANG II-induced wasting in vivo.