Transcription factor FoxO1, the dominant mediator of muscle wasting in chronic kidney disease, is inhibited by microRNA-486.
Transcription factor FoxO1, the dominant mediator of muscle wasting in chronic kidney disease, is inhibited by microRNA-486.
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DOI：
10.1038/ki.2012.84
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发表时间：
2012-08
影响因子：
19.6
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慢性肾脏疾病（CKD）通过激活E3连接酶、Atrogin-1/MaFbx和MuRF-1来刺激泛素蛋白酶体系统，从而加速肌肉蛋白的降解。叉头转录因子（FoxO）可以控制这些E3连接酶的表达，但个体FoxO对肌肉萎缩的贡献尚不清楚。为了研究这一点，我们创造了具有肌肉特异性fox01缺失的小鼠。fox01的缺失阻断了70%的由CKD诱导的E3连接酶的增加，以及蛋白质水解和肌肉质量的损失。因此，fox01在控制泛素蛋白酶体系统相关的蛋白水解中起作用。据报道，microRNA (miR)-486可以抑制FoxO1的表达及其活性，因此我们将miR-486模拟物转染到肌管原代培养物中，发现它可以阻断地塞米松刺激的蛋白质降解，而不影响蛋白质合成。它还通过下调PTEN磷酸酶（p-Akt的负调节因子）来降低FoxO1蛋白的翻译并增加FoxO1磷酸化。为了测试其在体内的功效，我们将miR-486电穿孔到肌肉中，发现尽管CKD， E3连接酶的表达被抑制，肌肉质量增加。因此，FoxO1是ckd诱导的肌肉萎缩的主要介质，miR-486协调降低FoxO1和PTEN以防止这种分解代谢反应。
Chronic kidney disease (CKD) accelerates muscle protein degradation by stimulating the ubiquitin proteasome system through activation of the E3 ligases, Atrogin-1/MaFbx and MuRF-1. Forkhead transcription factors (FoxO) can control the expression of these E3 ligases, but the contribution of individual FoxOs to muscle wasting is unclear. To study this we created mice with a muscle-specific FoxO1 deletion. The absence of FoxO1 blocked 70% of the increase in E3 ligases induction by CKD as well as the proteolysis and loss of muscle mass. Thus, FoxO1 has a role in controlling ubiquitin proteasome system-related proteolysis. Since microRNA (miR)-486 reportedly dampens FoxO1 expression and its activity, we transfected a miR-486 mimic into primary cultures of myotubes and found this blocked dexamethasone-stimulated protein degradation without influencing protein synthesis. It also decreased FoxO1 protein translation and increased FoxO1 phosphorylation by down-regulation of PTEN phosphatase, a negative regulator of p-Akt. To test its efficacy in vivo, we electroporated miR-486 into muscles and found expression of the E3 ligases was suppressed and muscle mass increased despite CKD. Thus, FoxO1 is a dominant mediator of CKD-induced muscle wasting and miR-486 coordinately decreases FoxO1 and PTEN to protect against this catabolic response.