Extraocular muscle aging: Functional and genomic changes

描述：(申请人摘要)骨骼丧失行为能力的后果 当肌肉群优先出现时，肌肉老化更加明显 受影响。眼外肌(EOMS)表现出丰富的 线粒体，高钙含量，几乎恒定的活动，并且是 优先针对与氧化应激有关的条件 如慢性进行性眼外肌麻痹和相关疾病。这 该项目旨在证明EOMS特别容易受到 年龄效应，可作为研究骨骼肌的模型 衰老。在衰老机制分析中，对异常细胞的研究 或组织反应可能被证明在理解 诺曼。揭示EOMS明显易感的机制 衰老应该有助于了解骨骼肌衰老的两种机制 以及姑息或预防性干预。总体假设是， 高线粒体含量和EOMS的活动率导致更大的 产生活性氧物种(ROS)，并使这些肌肉 特别容易受到年龄相关的功能丧失的影响。具体目标1将 观察年龄如何改变大鼠EOMS中ROS的产生。假设 EOMS在一生中以更高的速率产生ROS将在 三个年龄段(6、18和30mo)的氧化应激生化指标。 具体目标2将分析年龄对收缩特性的影响和 大鼠EOMS的钙处理能力。EOM功能的假说 会随着年龄的增长而恶化，因为钙的处理能力会丧失 通过研究细胞内游离钙在收缩过程中的动力学进行测试 用显微荧光法测定单个肌肉纤维的活性，以及收缩 完整的EOMS和部分骨骼肌的体外特性。具体目标3 将评估年龄对大鼠EOM基因转录的影响。假说 在EOMS中，年龄对基因表达的影响比其他人更大 骨骼肌将使用基因芯片技术进行测试。结果是 该项目将确定终身氧化应激是否是一种 对EOMS的重要有害影响，并可能证明这一点 肌群是研究骨骼肌衰老的一种可行模型。

DESCRIPTION: (Applicant's Abstract) The incapacitating consequences of skeletal muscle aging are even more obvious when a muscle group is preferentially affected. The extraocular muscles (EOMs) present a combination of abundant mitochondria, high calcium content, and almost constant activity, and are preferentially targeted by conditions that have been linked to oxidative stress like chronic progressive external ophthalmoplegia and related disorders. This project intends to demonstrate that the EOMs are particularly vulnerable to the effects of age, and may be used as a model for the study of skeletal muscle aging. In the analysis of aging mechanisms, the study of the exceptional cell or tissue response may prove to be of considerable value in understanding the norm. Uncovering the mechanisms for the apparent susceptibility of the EOMs to aging should contribute to knowledge of both skeletal muscle aging mechanisms and palliative or preventive interventions. The overall hypothesis is that the high mitochondrial content and activity rates of EOMs lead to greater generation of reactive oxygen species (ROS), and render these muscles exceptionally susceptible to age-related loss of function. Specific Aim 1 will detennine how age alters the generation of ROS in rat EOMs. The hypothesis that EOMs produce ROS at a higher rate throughout life will be tested in rats of three ages (6-, 18- and 30mo) with biochemical indices of oxidative stress. Specific Aim 2 will analyze the effect of age on contractile properties and calcium handling capacity of rat EOMs. The hypothesis that the function of EOM deteriorates with age because of loss of calcium handling capacity will be tested by studying the kinetics of free cytosolic calcium during contractile activity in single muscle fibers using microfluorometry, and the contractile properties of whole EOMs and selected skeletal muscles in vitro. Specific Aim 3 will evaluate the effect of age on rat EOM gene transcription. The hypothesis that age alters gene expression in EOMs to a greater extent than in other skeletal muscles will be tested using cDNA microarray technology. The results from this project will establish whether life-long oxidative stress is an important deleterious influence on the EOMs, and may prove this particular muscle group is a viable model for the study of skeletal muscle aging.