Molecular Mechanisms of Age-related Muscle Loss

与年龄相关的骨骼肌萎缩，也称为肌萎缩症，会降低老年人的健康和生活质量 很多老病人。然而，与年龄相关的肌肉萎缩的分子机制尚不清楚。 明白，而且药物疗法并不存在。因此，许多老年退伍军人遭受着 肌肉萎缩的后果，包括虚弱、活动障碍、摔倒、长期住院、 康复延迟，丧失独立生活能力，死亡率上升。这给……带来了巨大的负担 老年退伍军人、他们的家人和整个社会。重要的是，尽管其盛行和严重， 骨骼肌萎缩缺乏特异和有效的药物治疗，因此代表着巨大的 未得到满足的医疗需求。对肌肉萎缩的药物干预的发展一直受到以下因素的阻碍 事实上，肌肉萎缩的分子基础非常复杂，知之甚少，而且在很大程度上 未被开发的。这里提出的研究将有助于通过调查一项新发现的 骨骼肌纤维中的信号通路似乎对骨骼肌衰老至关重要。我们 最初是通过基于系统的不偏不倚的策略发现了这条途径，到目前为止，这些策略已经确定 几个关键的途径组件，包括转录调节因子ATF4(第一个也是唯一已知的 骨骼肌蛋白质的例子，它是失去力量、肌肉质量、肌肉质量和 老年耐力运动能力)、p21基因(老年骨骼肌中关键的ATF4靶基因)、 以及p21蛋白(一种新的肌肉纤维萎缩的介体)。我们建议的研究将建立在这些基础上 重要的初步发现，以更深入地研究和理解ATF4的激活机制 P21基因(AIM 1)，骨骼肌纤维中p21表达的病理生理后果(AIM 2)，以及p21促进肌肉萎缩的下游机制(S)(目标3)。通过这些 通过研究，我们希望阐明老年相关疾病的基本分子机制和新的治疗靶点 肌肉萎缩，这是一种影响许多退伍军人的致残情况。

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.