Extraocular muscle aging: Functional and genomic changes

描述：（申请人的摘要）骨骼损伤的失能后果 肌肉老化甚至更明显时，肌肉群是优先 影响。眼外肌（EOM）呈现丰富的 线粒体，高钙含量，几乎恒定的活动， 优先被与氧化应激有关的条件所靶向 如慢性进行性眼外肌麻痹和相关疾病。这 该项目旨在证明EOM特别容易受到 年龄的影响，并可用作骨骼肌研究的模型 衰老在衰老机制的分析中，研究异常细胞 或组织反应可能被证明是相当大的价值，在了解 norm.揭示了眼外膜对 衰老应该有助于了解骨骼肌衰老机制 以及姑息性或预防性干预。总的假设是， 较高线粒体含量和活性率的EOM导致更大的 产生活性氧（ROS），并使这些肌肉 特别容易出现与年龄相关的功能丧失。具体目标1将 确定年龄如何改变大鼠眼外肌中ROS的产生。的假设 EOM在整个生命过程中以更高的速率产生ROS，将在以下大鼠中进行测试： 3个月龄（6月龄、18月龄和30月龄），测定氧化应激生化指标。 具体目标2将分析年龄对收缩特性的影响， 大鼠眼外肌的钙处理能力。假设眼外肌的功能 随着年龄的增长，由于钙处理能力的丧失， 通过研究收缩过程中游离胞浆钙的动力学来测试， 使用显微荧光测定法测定单个肌纤维的活动， 在体外的整个眼外肌和选定的骨骼肌的性质。具体目标3 将评估年龄对大鼠EOM基因转录的影响。的假设 年龄改变EOM中的基因表达的程度比其他组织更大， 将使用cDNA微阵列技术测试骨骼肌。结果 从这个项目将确定是否终身氧化应激是一个 重要的有害影响的EOM，并可能证明这一点特别 肌群是研究骨骼肌衰老的可行模型。

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.