Molecular Mechanisms of Age-related Muscle Loss

年龄相关性肌肉损失的分子机制

• 批准号: 10084213
• 负责人: Mark A. Yorek
• 金额: --
• 依托单位: IOWA CITY VA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-07-01 至 2022-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10084213
• 关键词: Address; Affect; Age; Aging; Atrophic; Biochemical; Birth; CDK4 gene; CDKN1A gene; Complex; Critical Pathways; Data; Development; Elderly; Exhibits; Family; Fatigue; Fracture; Funding; Gene Expression; Gene Proteins; Genes; Genetic Transcription; Goals; Grant; Health; Hospitalization; Impairment; Independent Living; Intervention; Knockout Mice; Lead; Mediating; Mediator of activation protein; Medical; Medicine; Mitochondria; Molecular; Mus; Muscle; Muscle Fibers; Muscle Proteins; Muscle Weakness; Muscle function; Muscular Atrophy; Pathway interactions; Patients; Pharmacology; Prevalence; Protein Biosynthesis; Protein Kinase; Proteins; Quality of life; RNA Interference; Rehabilitation therapy; Repression; Repressor Proteins; Research; Resistance; Role; Severities; Signal Pathway; Skeletal Muscle; Societies; System; Testing; Transcription Regulatory Protein; Transcription Repressor; Veterans; Zinc Fingers; age related; age-related muscle loss; age-related muscle weakness; base; conditional knockout; cyclin D3; endurance exercise; exercise capacity; falls; in vivo; knock-down; middle age; mortality; mouse model; muscle aging; muscle form; new therapeutic target; novel; polyamine oxidase; prevent; sarcopenia; skeletal muscle wasting; small molecule; therapeutic target; young adult

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.

与年龄相关的骨骼肌萎缩，也称为肌肉减少症，降低了健康和生活质量 许多资深患者。但是，与年龄有关的肌肉萎缩的分子机制差 理解，并且不存在药理疗法。结果，许多老退伍军人遭受了 肌肉萎缩的后果，包括无力，活动受损，跌倒，住院时间长， 延迟康复，独立生活的丧失和死亡率增加。这使巨大负担负担 老年退伍军人，他们的家人和社会一般。重要的是，尽管其普遍性和严重性，但 骨骼肌萎缩缺乏特定有效的药理治疗，因此代表了巨大的 未满足的医疗需求。开发肌肉萎缩的药理学干预措施受到了阻碍 肌肉萎缩的分子基础是高度复杂，知名度不佳的事实，但仍在很大程度上 未探索。这里提出的研究将通过研究新确定的 骨骼肌纤维中的信号通路对于骨骼肌衰老至关重要。我们 最初通过公正的基于系统的策略发现了这一途径，迄今已确定 几个关键途径组件，包括转录调节器ATF4（第一个也是唯一已知的 骨骼肌蛋白的示例是损失强度，肌肉质量，肌肉质量和 衰老期间的耐力运动能力），p21基因（老年骨骼肌中的关键ATF4靶基因）， 和p21蛋白（一种新型的肌肉纤维萎缩介质）。我们提出的研究将以这些为基础 重要的初始发现，以更深入地研究和理解ATF4激活的机制 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（AIM 3）。通过这些 研究，我们希望阐明针对年龄相关的基本分子机制和新的治疗靶标 肌肉萎缩，一种影响许多老兵患者的残疾状况。