Angiotensin II upregulates protein phosphatase 2Cα and inhibits AMP-activated protein kinase signaling and energy balance leading to skeletal muscle wasting.
Angiotensin II upregulates protein phosphatase 2Cα and inhibits AMP-activated protein kinase signaling and energy balance leading to skeletal muscle wasting.
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DOI：
10.1161/hypertensionaha.111.174839
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发表时间：
2011-10
期刊：
影响因子：
--
通讯作者：
Delafontaine P
中科院分区：
文献类型：
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作者：
Tabony AM;Yoshida T;Galvez S;Higashi Y;Sukhanov S;Chandrasekar B;Mitch WE;Delafontaine P
充血性心力衰竭(CHF)和慢性肾脏病(CKD)的特点是血管紧张素II(Ang II)慢性升高和肌肉萎缩。血管紧张素II通过减少食欲和促进分解代谢而导致骨骼肌萎缩。丝氨酸/苏氨酸激酶5‘-单磷酸腺苷活化蛋白激酶(AMPK)主要作为细胞能量状态的感受器。它节省能源，有利于三磷酸腺苷的产生。我们推测，Ang II部分通过抑制AMPK信号通路和改变细胞能量平衡来诱导肌肉萎缩。我们的结果表明，血管紧张素II对小鼠的腓肠肌重量减少了26%，对ATP的消耗减少了74%。此外，血管紧张素II上调蛋白磷酸酶PP2Cα2.6倍，减少肌肉中AMPK的磷酸化和信号转导。重要的是，药理上的AMPK激动剂5-氨基咪唑-4-甲酰胺核糖核苷(AICAR)使AMPK活性恢复到配对喂养对照组的水平，并逆转了Ang II介导的ATP耗竭和肌肉萎缩。此外，AICAR激活Akt并抑制Ang II诱导的E3泛素连接酶表达的增加。这些新的结果证明了能量消耗和AMPK抑制在Ang II诱导的骨骼肌萎缩中的关键作用，并表明AMPK激活剂在以肌肉萎缩为特征的疾病中具有治疗潜力。
Congestive heart failure (CHF) and chronic kidney disease (CKD) are characterized by chronically elevated angiotensin II (Ang II) and muscle wasting. Ang II causes skeletal muscle wasting by reducing appetite and by enhancing catabolism. The serine/threonine kinase 5'-Adenosine Monophosphate Activated Protein Kinase (AMPK) functions mainly as a sensor of cellular energy status. It is energy sparing and favors ATP generation. We hypothesized that Ang II induces muscle wasting in part by inhibiting AMPK signaling and altering cellular energy balance. Our results show that Ang II infusion in mice reduced gastrocnemius muscle weight by 26% and depleted ATP by 74%. Further, Ang II upregulated the protein phosphatase PP2Cα by 2.6 fold and reduced AMPK phosphorylation and signaling in muscle. Importantly, the pharmacological AMPK activator 5-aminoimidazole-4-carboxamide ribonucleoside (AICAR) restored AMPK activity to levels of pair-fed controls and reversed Ang II-mediated ATP depletion and muscle wasting. Moreover, AICAR activated Akt and inhibited Ang II-induced increases in E3 ubiquitin ligase expression. These novel results demonstrate critical roles for energy depletion and AMPK inhibition in Ang II-induced skeletal muscle wasting, and suggest a therapeutic potential for AMPK activators in diseases characterized by muscle wasting.