Novel Signaling Pathways Underlying Skeletal Muscle Atrophy

项目摘要/摘要 骨骼肌萎缩会降低数千万人的健康和生活质量。原因： 肌肉萎缩包括衰老、肌肉废用、营养不良、危重疾病、某些药物和广泛的 一系列慢性病，包括癌症、心力衰竭、慢性阻塞性肺病、糖尿病、肾功能衰竭、肝硬变、类风湿 关节炎和艾滋病毒/艾滋病。肌肉萎缩的影响包括虚弱、活动障碍、跌倒、延长 住院、康复延迟、丧失独立生活能力和增加死亡率。重要的是，尽管 骨骼肌萎缩的患病率和严重程度缺乏特异有效的药物治疗和治疗。 因此，这代表着巨大的未得到满足的医疗需求。肌肉的药理干预研究进展 肌肉萎缩的分子基础非常复杂，很差，这一事实阻碍了肌肉萎缩 可以理解，但在很大程度上仍未被探索。这里提出的研究将有助于通过以下方式解决这个问题 研究骨骼肌纤维中应激诱导的分子信号通路 在至少3种临床重要情况下，肌肉萎缩是必要和充分的(老化， 固定和禁食)。我们最初是通过基于无偏见的系统发现这条途径的 战略，到目前为止，已经确定了几个关键的途径组成部分，包括Gadd45a( 途径的核心)、ATF4(Gadd45a基因的重要上游调节因子)和MEKK4(一种 Gadd45a蛋白的重要下游介体)。我们建议的研究将建立在这些重要的基础上 更深入地研究和了解控制Gadd45a的上游机制的初步发现 表达(目标1)，Gadd45a在肌肉中表达的病理生理后果(目标2)，以及 Gadd45A促进肌肉萎缩的下游机制(S)(目标3)。这些研究应该 极大地提高了我们对肌肉萎缩如何在分子水平上发生的理解，并促进了 实现几个较长期目标，最重要的是开发新的治疗方法 减少患病、受伤和/或老年人肌肉无力和萎缩的方法。

PROJECT SUMMARY / ABSTRACT Skeletal muscle atrophy diminishes the health and quality of life of tens of millions of people. Causes of muscle atrophy include aging, muscle disuse, malnutrition, critical illness, certain medications, and a wide range of chronic illnesses including cancer, heart failure, COPD, diabetes, renal failure, cirrhosis, rheumatoid arthritis, and HIV/AIDS. Effects of muscle atrophy include weakness, impaired activity, falls, prolonged hospitalization, delayed rehabilitation, loss of independent living, and increased mortality. Importantly, despite its prevalence and severity, skeletal muscle atrophy lacks a specific and effective pharmacologic therapy and thus represents an enormous unmet medical need. Development of pharmacologic interventions for muscle atrophy has been hindered by the fact that the molecular basis of muscle atrophy is highly complex, poorly understood, and still largely unexplored. The research proposed here would help to address this issue by investigating a stress-inducible molecular signaling pathway in skeletal muscle fibers that appears to be necessary and sufficient for muscle atrophy during at least 3 clinically important scenarios (aging, immobilization and fasting). We originally discovered this pathway through unbiased systems-based strategies, which have, to date, identified several critical pathway components, including Gadd45a (the pathway's centerpiece), ATF4 (an essential upstream regulator of the Gadd45a gene), and MEKK4 (an important downstream mediator of the Gadd45a protein). Our proposed studies will build upon these important initial findings to more deeply investigate and understand the upstream mechanisms that control Gadd45a expression (Aim 1), the pathophysiological consequences of Gadd45a expression in muscle (Aim 2), and the downstream mechanism(s) by which Gadd45a promotes muscle atrophy (Aim 3). These studies should significantly advance our understanding of how muscle atrophy occurs at the molecular level and facilitate achievement of several longer-term goals, the most important being the development of new therapeutic approaches for reducing muscle weakness and atrophy in people who are ill, injured and/or aged.