Extraocular muscle aging: Functional and genomic changes

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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.