Atrogin-1 and Muscle Protein Balance

描述(由申请人提供)：肌肉萎缩是包括糖尿病和肾功能衰竭在内的许多疾病的衰弱特征。我们最初确定阿托金-1是一种基因，在各种疾病动物模型的肌肉萎缩过程中强烈诱导。它的缺失可以保护肌肉免受萎缩。在发现后的七年里，该基因的上调已经成为定义萎缩状态的一个主要生物标志物。Atrogin-1是泛素-蛋白质连接酶的一个组成部分，它催化关键蛋白质的降解，导致肌肉萎缩。在过去的研究期间，我们在了解导致萎缩肌肉中阿托金-1诱导的信号通路方面取得了很大进展。最初我们认为该基因只在骨骼肌和心肌中表达，并且只与这些组织的萎缩有关。然而，我们最近的数据表明，阿托金-1具有更多的细胞功能，在HMG CoA还原酶抑制剂(他汀类)对骨骼肌的毒性以及分娩后子宫的正常复旧中发挥关键作用。这项建议通过研究在临床重要的生理和病理过程中诱导阿托金-1的途径，继续我们对阿托金-1功能的探索。我们将在培养的肌肉细胞、斑马鱼和小鼠中建立他汀类药物毒性模型，并确定参与阿托金-1表达的信号通路和前烯基化蛋白中间体。我们将利用我们的阿托金-1基因敲除小鼠群体来研究阿托金-1缺失在他汀类肌病发生中的作用。为了了解阿托金-1如何促进蛋白质分解和肌肉损伤，我们将确定它在萎缩过程中在细胞核中的作用。阐明阿托金-1的功能将有助于表征肌肉蛋白质分解的机制和生理调节，还可能开发出治疗肌肉萎缩状况及其相关发病率的药物抑制剂。与公共健康相关：Atrogin-1是触发肌肉蛋白质破坏的复合体的一部分，它的激活会导致肌肉萎缩。我们的新数据表明，阿托品-1具有更广泛的功能，在降胆固醇药物(他汀类药物)的毒性中发挥关键作用。这一建议通过研究在这些条件下激活阿托金-1的途径来继续我们对阿托金-1功能的探索。这些对阿托金-1功能的研究将有助于阐明身体如何调节肌肉大小，并最终导致抗击肌肉萎缩的药物的开发。

DESCRIPTION (provided by applicant): Muscle wasting is a debilitating feature of many disease states including diabetes and renal failure. We initially identified atrogin-1 as a gene that is strongly induced during muscle wasting in various animal models of disease. Its absence protects muscles from atrophy. In the seven years since its discovery, upregulation of this gene has become a major biomarker defining the atrophy state. Atrogin-1 acts as one component of a ubiquitin-protein ligase that catalyzes the degradation of key proteins, leading to muscle wasting. During the past study period; we made large strides in understanding the signaling pathways that lead to atrogin-1 induction in atrophying muscle. Initially we had believed this gene was only expressed in skeletal and cardiac muscle, and only involved in atrophy of these tissues. Our recent data, however, has shown that atrogin-1 has more diverse cellular functions, playing a critical role in the skeletal muscle toxicity of HMG CoA reductase inhibitors (statins) and in the normal involution of the uterus following delivery. This proposal continues our exploration of atrogin-1 function by studying the pathways that induce atrogin-1 in clinically important physiological and pathological processes. We shall develop models of statin toxicity in cultured muscle cells, zebrafish and mice, and identify the signaling pathways and prenylated protein intermediates involved in atrogin-1 expression. We shall utilize our colony of atrogin-1 knockout mice to study the effects of atrogin-1 absence in the development of statin myopathy. In an effort to understand how atrogin-1 promotes protein breakdown and muscle damage, we will identify its role in the nucleus during atrophy. Elucidating the functions of atrogin-1 will help characterize the mechanisms and physiological regulation of muscle protein breakdown and may also allow the development of pharmacological inhibitors that could combat muscle wasting conditions and their associated morbidity. PUBLIC HEALTH RELEVANCE: Atrogin-1 is part of a complex that triggers the destruction of muscle proteins, and its activation leads to muscle wasting. Our new data suggests that atrogin-1 has broader functions, playing a critical role in the toxicity of cholesterol-lowering medications (statins). This proposal continues our exploration of atrogin-1 function by studying the pathways that activate atrogin-1 in these conditions. These studies of atrogin-1 function will help elucidate how the body regulates muscle size, and will ultimately lead to development of drugs to combat muscle wasting.