Determinants of extraocular muscle function

描述（由申请人提供）：眼运动系统可以说是最了解的哺乳动物运动系统。然而，眼外肌，它的执行臂，仍然有点像一个黑盒子。从特殊的表型和极端的功能特征，到对某些神经肌肉疾病的不同反应，这些小肌肉偏离了骨骼肌的刻板印象。我们的结果表明，眼外肌的代谢途径被认为对其他骨骼肌至关重要的替代安排。此外，我们的初步研究表明，它们的线粒体也具有独特的特性，这一事实可能解释了它们对一些线粒体肌病的易感性。在这个项目中，我们将测试线粒体在眼外肌中的功能不同，它们的含量和性质由视觉经验决定，并随着年龄的变化而改变的假设。我们将把成熟的功能和生化分析与视觉剥夺和衰老模型相结合，以实现以下目标：(1)确定限制眼外肌线粒体功能的因素；(2)检验眼外肌线粒体含量和功能是否受出生后视觉体验的影响；(3)确定衰老如何改变眼外肌线粒体含量和功能。这些结果将解决我们对眼外肌基本生物学理解中的三个重要空白：眼外肌线粒体的功能特性、眼外肌产后代谢特性的发展以及眼外肌衰老。因此，我们期望新的知识将适用于年轻人（斜视）和老年人（线粒体肌病）的眼运动障碍。公共卫生相关性：该项目将研究细胞的细胞能量工厂线粒体在移动眼睛的小肌肉中有何不同。它还将证明，生命早期的正常视力对眼部肌肉达到产生能量和维持高活动水平的能力是非常重要的。最后，这些研究将探讨衰老对眼肌功能的有害影响。

DESCRIPTION (provided by applicant): The ocular motor system is arguably the best understood mammalian motor system. However, the extraocular muscles, its effector arms, remain somewhat of a black box. From a peculiar phenotype and extreme functional profile, to a disparate response to some neuromuscular disorders, these small muscles deviate from the skeletal muscle stereotype. Our results have demonstrated that the extraocular muscles have alternative arrangements for metabolic pathways considered vital for other skeletal muscles. Moreover, our pilot studies suggest that their mitochondria have unique properties as well, a fact that may explain their susceptibility to some mitochondrial myopathies. In this project, we will test the hypothesis that mitochondria are functionally different in the extraocular muscles and their content and properties are determined by visual experience and altered by aging. We will combine well-established functional and biochemical assays with models of visual deprivation and aging to achieve the following aims: (1) determine the factors that limit mitochondrial function in the extraocular muscles; (2) test whether extraocular muscle mitochondrial content and function are influenced by postnatal visual experience; and (3) determine how aging alters mitochondrial content and function in the extraocular muscles. The results will address three important gaps in our understanding of the basic biology of the extraocular muscles: the functional properties of their mitochondria, the development of their metabolic properties in the postnatal period, and aging. Therefore, we expect that the new knowledge will be applicable to disorders of ocular motility in the young (strabismus) and the aged (mitochondrial myopathies). PUBLIC HEALTH RELEVANCE: This project will study how the mitochondria, the cellular energy factories of the cells, are different in the small muscles that move the eyes. It will also demonstrate how normal vision early in life is very important to allow the eye muscles to achieve their capacity to generate energy and sustain high activity levels. Finally, these studies will explore the deleterious consequences of aging on eye muscle function.