Atrogin-1 and Muscle Protein Balance

描述（由申请人提供）：肌肉萎缩是许多疾病状态的衰弱特征，包括糖尿病和肾衰竭。我们最初发现，在各种疾病的动物模型中，atrogin-1是一种在肌肉萎缩过程中被强烈诱导的基因。它的缺失可以防止肌肉萎缩。自发现以来的七年中，该基因的上调已成为定义萎缩状态的主要生物标志物。抗衰老素-1作为泛素蛋白连接酶的一个组成部分，催化关键蛋白质的降解，导致肌肉萎缩。在过去的学习期间；我们在理解导致萎缩肌肉中atroggin -1诱导的信号通路方面取得了重大进展。最初我们认为这个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，阿特龙-1具有更多样化的细胞功能，在HMG辅酶a还原酶抑制剂（他汀类药物）的骨骼肌毒性和分娩后子宫正常复归中发挥关键作用。本研究通过研究atrogin-1在临床重要生理和病理过程中的诱导通路，继续探索atrogin-1的功能。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atroggin -1表达的信号通路和烯丙基化蛋白中间体。我们将利用我们的抗血小板素-1敲除小鼠群体来研究抗血小板素-1缺失在他汀类肌病发展中的作用。为了了解atroggin -1如何促进蛋白质分解和肌肉损伤，我们将确定其在萎缩期间在细胞核中的作用。阐明atrogin-1的功能将有助于表征肌肉蛋白分解的机制和生理调节，也可能有助于开发对抗肌肉萎缩及其相关疾病的药理学抑制剂。公共卫生相关性：atrogin1是触发肌肉蛋白破坏的复合物的一部分，它的激活导致肌肉萎缩。我们的新数据表明，阿特罗金-1具有更广泛的功能，在降胆固醇药物（他汀类药物）的毒性中起着关键作用。这一建议通过研究在这些条件下激活atrogin-1的途径，继续我们对atrogin-1功能的探索。这些关于atrogin1功能的研究将有助于阐明人体如何调节肌肉大小，并最终导致对抗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.