Molecular Mechanisms of Age-related Muscle Loss

年龄相关性肌肉损失的分子机制

• 批准号: 10368017
• 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/10368017
• 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，会降低人们的健康和生活质量 许多老患者。然而，与年龄相关的肌肉萎缩的分子机制尚不清楚。 理解，并且不存在药物治疗。结果，许多老年退伍军人遭受了 肌肉萎缩的后果，包括虚弱、活动受损、跌倒、长期住院、 康复延迟、丧失独立生活以及死亡率增加。这给大家带来了巨大的负担 老年退伍军人、他们的家人和整个社会。重要的是，尽管其普遍存在且严重， 骨骼肌萎缩缺乏特异性和有效的药物治疗，因此代表着巨大的 未满足的医疗需求。肌肉萎缩药物干预措施的发展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，人们对其知之甚少，而且仍然在很大程度上 未经探索。这里提出的研究将通过调查新发现的一种物质来帮助解决这个问题 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 最初通过公正的基于系统的策略发现了这条途径，迄今为止，该策略已确定 几个关键的通路组件，包括转录调节因子 ATF4（第一个也是唯一一个已知的 骨骼肌蛋白的例子，它是力量、肌肉质量、肌肉质量和力量损失所必需的 衰老过程中的耐力运动能力）、p21 基因（老年骨骼肌中关键的 ATF4 靶基因）、 和 p21 蛋白（一种新型的肌纤维萎缩介质）。我们提出的研究将建立在这些基础上 重要的初步发现可以更深入地研究和理解 ATF4 激活的机制 p21 基因（目标 1），骨骼肌纤维中 p21 表达的病理生理学后果（目标 2) 以及 p21 促进肌肉萎缩的下游机制（目标 3）。通过这些 研究，我们希望阐明年龄相关的基本分子机制和新的治疗靶点 肌肉萎缩是一种影响许多退伍军人患者的致残性疾病。