MECHANISMS OF MUSCLE AGING--ANALYSIS AND INTERVENTION

肌肉衰老的机制——分析与干预

• 批准号: 2696835
• 负责人: Nadia A Rosenthal
• 金额: $ 8.74万
• 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/2696835
• 关键词: MECHANISMS; MUSCLE; AGING; ANALYSIS; INTERVENTION

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：骨骼肌的力量和功能下降， 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不是 清楚肌肉质量的损失以及力量和力量的下降 衰老期间的输出伴随着选择性减少， 肌肉纤维大小，纤维成分的变化，以及几个 生理参数缺乏有关肌肉的信息 与生肌发育相反，衰老是由于缺乏数据 关于肌肉纤维类型的调节。另外仅有 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，并且可以在不同的时间受到干扰。 生命周期的各个阶段。该项目的目的之一是 开发合适的实验系统，用于识别 衰老肌肉的性质，这可能导致观察到的缺陷， 性能，并研究相关的结构和生理 衰老过程中基因表达的变化 动物研究人员将确定潜在的遗传途径 骨骼肌年龄相关的变化，建立转基因系统， 测试肌肉衰老的分子模型， 扭转或减轻老龄化对人口的累积影响的战略 骨骼肌性能。 该项目的四名研究人员有一个共同的兴趣， 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，罗森塔尔博士将研究 肌源性发育过程中单个肌纤维类型的起源，以及 将在衰老的动物体内追踪它们的命运她会用病毒 和转基因方法来开发肌肉衰老模型， 切除特定的肌肉纤维在第二单元斯威尼博士将使用 转基因方法来调节肌肉中的机械损伤， 降低氧自由基水平，然后评估 适应目标纤维类型的功能缺陷。在第三单元， 博士Balice-Gordon将研究通过以下方法来改变衰老性肌肉萎缩的方法： 病毒和转基因递送选定的生长因子和激素 受体使用病毒和转基因传递系统。在第4单元，博士。 休斯将建立SKI癌基因的分子机制， 产生纤维特异性肥大，并以此为模型， 肌肉衰老的减弱。他将使用一种新的逆转录病毒 输送系统。 该项目还拥有核心设施， laboratories.转基因动物和病毒核心（核心C），在 休斯博士的指导，位于弗雷德里克的NCI设施， 马里兰州。这一设施将简化生产和分析， 转基因动物，以允许体内老化的快速测试 模型形态学和生理学核心（核心B），由Dr. 凯利和斯威尼在UP，将提供结构和纤维类型 肌肉的分析，这是大多数人的基本组成部分， 项目一个行政核心（核心A），位于MGH下， 罗森塔尔博士的指导下，将使用在心血管资源 研究中心和MGH-East动物设施计划和实施 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。