Muscle-specific expression of IGF-1 blocks angiotensin II-induced skeletal muscle wasting
Muscle-specific expression of IGF-1 blocks angiotensin II-induced skeletal muscle wasting
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DOI：
10.1172/jci200522324
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发表时间：
2005-02-01
影响因子：
15.9
通讯作者：
Delafontaine, P
中科院分区：
文献类型：
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作者：
Song, YH;Li, YX;Delafontaine, P
晚期充血性心力衰竭与肾素-血管紧张素系统激活和骨骼肌萎缩相关。我们以前表明，血管紧张素11输注大鼠产生恶病质继发于肌肉蛋白水解增加，也降低了循环和骨骼肌IGF-1的水平。在这里，我们表明，血管紧张素II显着下调磷酸化Akt和激活caspase-3在骨骼肌，导致肌动蛋白裂解，肌肉蛋白水解的重要组成部分，并增加细胞凋亡。这些变化被IGF-1的肌肉特异性表达阻断，可能通过Akt/mTOR/p70 S6 K信号通路。我们还表明，泛素连接酶atrogin-1和肌肉环指-1的mRNA水平上调血管紧张素II输注WT，但不是在IGF-1转基因小鼠。这些发现强烈表明，骨骼肌中IGF-1的血管紧张素II下调与血管紧张素II诱导的消瘦有因果关系。由于肾素-血管紧张素系统在许多分解代谢条件下被激活，我们的研究结果对理解骨骼肌萎缩的机制具有广泛的意义，并为新的治疗方法提供了理论基础。
Advanced congestive heart failure is associated with activation of the renin-angiotensin system and skeletal muscle wasting. We previously showed that angiotensin 11 infusion in rats produces cachexia secondarily to increased muscle proteolysis and also decreases levels of circulating and skeletal muscle IGF-1. Here we show that angiotensin II markedly downregulates phospho-Akt and activates caspase-3 in skeletal muscle, leading to actin cleavage, an important component of muscle proteolysis, and to increased apoptosis. These changes are blocked by muscle-specific expression of IGF-1, likely via the Akt/mTOR/p70S6K signaling pathway. We also demonstrate that mRNA levels of the ubiquitin ligases atrogin-1 and muscle ring finger-1 are upregulated in angiotensin II-infused WT, but not in IGF-1-transgenic, mice. These findings strongly suggest that angiotensin II downregulation of IGF-1 in skeletal muscle is causally related to angiotensin II-induced wasting. Because the renin-angiotensin system is activated in many catabolic conditions, our findings have broad implications for understanding mechanisms of skeletal muscle wasting and provide a rationale for new therapeutic approaches.