MECHANISMS OF MUSCLE AGING--ANALYSIS AND INTERVENTION

描述：骨骼肌力量和功能的下降， 再加上它的适应性的限制是衰老的一个标志 哺乳动物。然而，这种肌肉衰老的分子基础并不是 安全。肌肉质量的减少，力量和力量的下降 衰老期间的产量伴随着选择性的减少 肌肉纤维的大小，纤维成分的变化，以及几个 生理参数。关于肌肉的信息匮乏 衰老，而不是肌源性发育，是由于缺乏数据 关于肌肉纤维类型的调节。此外，只有 无效的体内系统可用于测试基因程序，这些程序 可能会影响肌肉衰老，而这可以在不同的 生命周期的各个阶段。该计划项目的一个目的是 开发合适的实验系统来识别内在的 衰老肌肉的特性，这可能导致观察到的缺陷 性能，并调查相关的结构和生理 通过干扰衰老中的基因表达参与衰老的参数 动物。研究人员将确定潜在的遗传途径 骨骼肌的年龄相关变化，建立转基因系统 测试肌肉衰老的分子模型，并测试干预性 逆转或减弱衰老累积影响的策略 骨骼肌表现。 方案项目中的四名调查人员对 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 在肌原发育过程中个体肌肉纤维类型的起源 然后会在老化的动物身上追踪它们的命运。她会用这两种病毒 以及通过转基因方法建立肌肉衰老模型 消融特定的肌肉纤维。在第二单元，斯威尼博士将使用 转基因方法学调控肌肉机械损伤的研究进展 降低氧自由基水平，然后评估 适应靶向纤维类型的功能缺陷。在单元3中， 巴利斯-戈登博士将研究通过以下方式改善衰老肌肉萎缩的方法 携带特定生长因子和激素的病毒和转基因 使用病毒和转基因递送系统的受体。在第四单元，Dr。 休斯将建立SKI癌基因的分子机制 产生纤维特有的肥大，并将其用作 延缓肌肉衰老。他将使用一种新型的逆转录病毒 传送系统。 该项目还拥有核心设施，可供 实验室。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。该设施将简化生产和分析 转基因动物允许快速检测体内衰老 模特们。形态和生理核心(核心B)，由Dr。 凯利和斯威尼在UP，将提供结构和纤维类型 肌肉分析，这是大多数 项目。行政核心(核心A)，位于MGH的 在罗森塔尔博士的指导下，将使用心血管系统的资源 研究中心和MGH-EAST动物设施的规划和实施 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 在实验室之间交换动物和试剂。

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.