Molecular Mechanisms of Age-related Muscle Loss

与骨骼肌相关的骨骼肌萎缩，也称为肌肉减少症，降低了健康和生活质量， 很多老患者。然而，与年龄相关的肌肉萎缩的分子机制还很差， 了解，并且不存在药物治疗。因此，许多老年退伍军人遭受 肌肉萎缩的后果，包括虚弱、活动受损、福尔斯、住院时间延长， 延迟康复、丧失独立生活和增加死亡率。这给我们带来了巨大的负担， 老年退伍军人，他们的家庭和整个社会。重要的是，尽管它的流行和严重性， 骨骼肌萎缩缺乏特异性和有效的药物治疗， 未满足的医疗需求肌肉萎缩的药物干预的发展受到阻碍， 事实上，肌肉萎缩的分子基础是高度复杂的，知之甚少， 未开发的这里提出的研究将有助于通过调查新发现的 在骨骼肌纤维的信号通路，似乎是至关重要的骨骼肌老化。我们 最初是通过无偏见的基于系统的策略发现这一途径的，到目前为止， 几个关键途径的组成部分，包括转录调节因子ATF4（第一个也是唯一已知的 骨骼肌蛋白质的实例，其是丧失力量、肌肉质量、肌肉质量和 衰老过程中的耐力运动能力），p21基因（老年骨骼肌中的关键ATF 4靶基因）， 和p21蛋白（肌纤维萎缩的新介质）。我们建议的研究将建立在这些基础上 重要的初步发现，以更深入地研究和了解ATF4激活的机制 p21基因（目的1），p21在骨骼肌纤维中表达的病理生理后果（目的 2），以及p21促进肌肉萎缩的下游机制（目的3）。通过这些 研究，我们希望阐明基本的分子机制和新的治疗目标，年龄相关的 肌肉萎缩，一种影响许多退伍军人患者的致残性疾病。

Age-related skeletal muscle atrophy, also known as sarcopenia, diminishes the health and quality of life of many Veteran patients. However, the molecular mechanisms of age-related muscle atrophy are poorly understood, and a pharmacologic therapy does not exist. As a result, many elderly Veterans suffer the consequences of muscle atrophy, including weakness, impaired activity, falls, prolonged hospitalization, delayed rehabilitation, loss of independent living, and increased mortality. This places enormous burdens on elderly Veterans, their families, and society in general. 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 newly identified signaling pathway in skeletal muscle fibers that appears to be critically important for skeletal muscle aging. We originally discovered this pathway through unbiased systems-based strategies, which have, to date, identified several critical pathway components, including the transcriptional regulator ATF4 (the first and only known example of a skeletal muscle protein that is required for the loss of strength, muscle quality, muscle mass and endurance exercise capacity during aging), the p21 gene (a key ATF4 target gene in elderly skeletal muscle), and the p21 protein (a novel mediator of muscle fiber atrophy). Our proposed studies will build upon these important initial findings to more deeply investigate and understand the mechanisms by which ATF4 activates the p21 gene (Aim 1), the pathophysiological consequences of p21 expression in skeletal muscle fibers (Aim 2), and the downstream mechanism(s) by which p21 promotes muscle atrophy (Aim 3). Through these studies, we hope to elucidate fundamental molecular mechanisms and new therapeutic targets for age-related muscle atrophy, a disabling condition that affects many Veteran patients.