MECHANISMS OF MUSCLE AGING--ANALYSIS AND INTERVENTION

肌肉衰老的机制——分析与干预

• 批准号: 2055298
• 负责人: Nadia A Rosenthal
• 金额: $ 84.78万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 1995
• 资助国家: 美国
• 起止时间: 1995-09-01 至 2000-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2055298
• 关键词: aging; muscle function; striated muscles

DESCRIPTION: A decline in both strength and function in skeletal muscle, plus a restriction of its adaptability is a hallmark of aging in mammals. However, the molecular basis of this muscle senescence is not clear. The loss in muscle mass and a decrease in strength and force output during senescence is accompanied by a selective reduction in muscle fiber size, shifts in fiber composition, and changes in several physiological parameters. The paucity of information concerning muscle aging, as opposed to myogenic development, is due to a lack of data concerning the regulation of muscle fiber types. In addition, only ineffective in vivo systems are available to test gene programs which may affect muscle senescence and which can be perturbed at different stages of the life cycle. One purpose of this program project is to develop suitable experimental systems for identifying the intrinsic properties of senescent muscle which may cause the observed deficits in performance, and to investigate relevant structural and physiological parameters involved in senescence by perturbing gene expression in aging animals. The investigators will define the genetic pathways underlying age-related changes in skeletal muscle, establish transgenic systems for testing molecular models of muscle senescence, and test interventional strategies to reverse or attenuate the cumulative effects of aging on skeletal muscle performance. The four investigators in the program project have a common interest in muscle biology. Their areas of research include skeletal muscle biochemistry, physiology and molecular biology, as well as retrovirology and transgenic technology. In unit 1, Dr. Rosenthal will study the origin of individual muscle fiber types during myogenic development, and will then track their fate in the aging animal. She will use both viral and transgenic approaches to develop models of muscle senescence by ablating specific muscle fibers. In unit 2, Dr. Sweeney will use transgenic methodology to modulate the mechanical damage in muscle by decreasing the levels of oxygen free radicals, and then assess adaptation to functional deficits in targeted fiber types. In unit 3, Dr. Balice-Gordon will study ways to modify senescent muscle atrophy by viral and transgenic delivering selected growth factors and hormone receptors using viral and transgenic delivery systems. In unit 4, Dr. Hughes will establish the molecular mechanisms by which the ski oncogene produces fiber-specific hypertrophy, and use this as a model for the attenuation of muscle senescence. He will use a novel retroviral delivery system. The project also has core facilities to be shared between the laboratories. A transgenic animal and virus core (Core C), under the guidance of Dr. Hughes, is located at the NCI facility at Frederick, Maryland. This facility will streamline the production and analysis of transgenic animals to allow the rapid testing of the in vivo aging models. A morphology and physiology core (Core B), operated by Drs. Kelly and Sweeney at the UP, will provide the structural and fiber type analysis of muscles, which is an essential component of most of the projects. An administrative core (Core A), located at the MGH under the guidance of Dr. Rosenthal, will use the resources at the Cardiovascular Research Center and the MGH-East Animal Facility to plan and implement routine meetings, conference calls and review sessions necessary to coordinate activities at the three research centers, and will coordinate exchange of animals and reagents between the laboratories.

描述：骨骼肌力量和功能下降， 加上其适应性的限制是衰老的标志 哺乳动物。然而，这种肌肉衰老的分子基础并不是 清除。肌肉质量损失以及力量和力量下降 衰老过程中的输出伴随着选择性减少 肌纤维大小、纤维成分的变化以及一些方面的变化 生理参数。缺乏有关肌肉的信息 与肌源性发育相反，衰老是由于缺乏数据造成的 关于肌纤维类型的调节。此外，仅 无效的体内系统可用于测试基因程序 可能会影响肌肉衰老，并且可能会在不同的情况下受到干扰 生命周期的阶段。该计划项目的目的之一是 开发合适的实验系统来识别内在的 衰老肌肉的特性可能会导致观察到的缺陷 性能，并研究相关的结构和生理 通过干扰衰老过程中的基因表达来参与衰老的参数 动物。研究人员将确定潜在的遗传途径 骨骼肌与年龄相关的变化，建立转基因系统 测试肌肉衰老的分子模型，并测试介入治疗 逆转或减弱衰老对身体的累积影响的策略 骨骼肌的性能。 该计划项目的四位研究者有一个共同的兴趣 肌肉生物学。他们的研究领域包括骨骼肌 生物化学、生理学和分子生物学以及逆转录病毒学 和转基因技术。在第一单元中，罗森塔尔博士将研究 肌原性发育过程中个体肌纤维类型的起源，以及 然后将追踪它们在衰老动物身上的命运。她将同时使用病毒 和转基因方法来开发肌肉衰老模型 消融特定的肌肉纤维。在第 2 单元中，Sweeney 博士将使用 转基因方法通过调节肌肉机械损伤 降低氧自由基的水平，然后评估 适应目标纤维类型的功能缺陷。在第 3 单元中， Balice-Gordon 博士将研究通过以下方式改变衰老肌肉萎缩的方法： 病毒和转基因提供选定的生长因子和激素 使用病毒和转基因递送系统的受体。在第 4 单元中，博士。 休斯将建立滑雪致癌基因的分子机制 产生纤维特异性肥大，并将其用作模型 肌肉衰老的减弱。他将使用一种新型逆转录病毒 输送系统。 该项目还拥有可供各公司共享的核心设施 实验室。转基因动物和病毒核心（核心C），在 Hughes 博士的指导，位于 Frederick 的 NCI 设施， 马里兰州。该设施将简化生产和分析 转基因动物可快速检测体内衰老情况 模型。形态学和生理学核心（核心 B），由博士操作。 UP 的 Kelly 和 Sweeney 将提供结构和纤维类型 肌肉分析，这是大多数运动的重要组成部分 项目。行政核心（核心 A），位于 MGH，隶属于 Rosenthal 博士的指导下，将使用心血管中心的资源 研究中心和麻省总医院东部动物中心负责规划和实施 必要的例行会议、电话会议和审查会议 协调三个研究中心的活动，并将协调 实验室之间交换动物和试剂。