Protein Nutrition in Experimental Uremia

导致肌肉质量丧失的代谢异常导致的发病率和死亡率 肾衰竭。我们的长期目标是确定尿毒症导致肌肉损失的机制，以便 设计新的疗法来解决这个问题。我们已经确定了产生肌肉蛋白质的新过程 损失：1)caspase-3的激活是分解肌肉屈服复杂结构的第一步。 被泛素系统降解的底物。2)肌肉加速流失的导火索是 IRS-1相关的磷脂酰肌醇3-激酶活性(IRS-1-PI3K)降低。减少IRS-1- PI3K刺激caspase-3和泛素系统，包括关键酶阿托金-1/MAFbx。3) 激活蛋白质降解途径绝对需要生理水平的糖皮质激素(GC)。 因此，我们提出了一个“两次打击”的过程：GC和被抑制的胰岛素反应协同抑制IRS-1- PI3K活性和启动肌肉蛋白分解。我们将使用实验模型来测试两个Hit模型；小鼠 肌肉中缺乏胰岛素或IGF-1受体。我们将利用转基因小鼠将我们的研究扩展到尿毒症 表现出IRS-1-PI3K通路的激活(例如，PTEN缺失、Akt或IGF-1)。具体来说，我们将：1) 测试GC和受损的胰岛素/IGF-1反应是否在刺激肌肉方面起着重要作用 胰岛素和/或胰岛素样生长因子-1受体缺陷小鼠的蛋白质分解，但仅在肌肉中；2) 探讨糖皮质激素和胰岛素/IGF-1缺乏对IRS-1-PI3K表达下调的作用机制 以及3)研究体内PI3K和Akt活性的操纵如何改变尿毒症- 利用转基因小鼠诱导肌肉蛋白分解。我们的结果的意义在于，两次命中模型 可以适用于许多情况，因为GC和胰岛素反应降低存在于许多分解代谢中 疾病，

Abnormalities in metabolism leading to loss of muscle mass contribute to the morbidity and mortality of kidney failure. Our long-term goal is to identify uremia-induced mechanisms causing muscle loss in order to devise novel therapies to combat this problem. We have identified new processes that cause muscle protein losses: 1) caspase-3 activation is the initial step that breaks down the complex structure of muscle yielding substrates that are degraded by the ubiquitin system. 2) The trigger that accelerated muscle loss is decreased activity of IRS-1 associated phosphatidylinositol 3-kinase activity (IRS-1-PI3K). Decreased IRS-1- PI3K stimulates caspase-3 and the ubiquitin system, including the critical enzyme, atrogin-1/MAFbx. 3) Physiological levels of glucocorticoids (GC) are absolutely required to activate protein degradation pathways. Thus, we propose a "two hit" process: GC and suppressed insulin responses synergistically suppress IRS-1- PI3K activity and initiate muscle proteolysis. We will test the two hit model using experimental models; mice lacking the insulin or IGF-1 receptor in muscle. We will extend our study to uremia using transgenic mice that exhibit activation of the IRS-1-PI3K pathway (e.g., PTEN deletion, Akt or IGF-1). Specifically, we will: 1) test if there is an essential role for both GC and impaired insulin/IGF-1 responses that stimulates muscle proteolysis in mice with deficiency of the insulin or the IGF-1 receptor or both receptors but only in muscle; 2) examine the mechanism for GC- and insulin/IGF-1 deficiency-dependent downregulation of IRS-1-PI3K activity in muscle; and 3) examine how manipulation of PI3K and Akt activities in vivo will change uremia- induced muscle proteolysis using transgenic mice. The significance of our results is that the two-hit model could apply to many conditions because GC and decreased insulin responses are present in many catabolic illnesses,