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/jci22324
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发表时间：
2005-02
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影响因子：
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通讯作者：
Yao‐Hua Song;Yangxin Li;Jie Du;W. Mitch;N. Rosenthal;P. Delafontaine
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作者：
Yao‐Hua Song;Yangxin Li;Jie Du;W. Mitch;N. Rosenthal;P. Delafontaine
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有关。我们先前发现，血管紧张素II在大鼠体内产生恶病质，继而导致肌肉蛋白分解增加，并降低循环和骨骼肌中IGF-1的水平。在这里，我们发现血管紧张素II显著下调骨骼肌中的磷酸化Akt并激活caspase-3，导致肌动蛋白裂解，这是肌肉蛋白分解的重要组成部分，并增加细胞凋亡。这些变化被肌肉特异性表达的IGF-1阻断，可能是通过Akt/mTOR/p70S6K信号通路。我们还证明，泛素连接酶阿托金-1和肌肉环指-1的mRNA水平在注射血管紧张素II的WT中上调，但在IGF-1转基因小鼠中不上调。这些发现有力地表明，血管紧张素II下调骨骼肌中IGF-1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，我们的发现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 II 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.