Interatction of Estrogen, Age and Activity on Musculoskeletal Strength in Females

描述(申请人提供)：骨骼肌功能的丧失会随着年龄的增长而发生，但女性和男性之间的丧失速度和程度存在差异的原因尚不清楚。女性的丢失可能与卵巢激素的变化有关，除了年龄的变化，但这些激素对骨骼肌的作用机制尚未阐明。本申请概述的研究的总体目标是确定荷尔蒙介导的导致老年女性肌肉力量丧失的机制。雌二醇是一种关键的卵巢激素，它影响关键收缩蛋白肌球蛋白的功能，而肌球蛋白又影响年轻成年雌性小鼠的肌肉力量，但雌二醇对老年雌性小鼠肌肉的影响尚不清楚。因此，这项应用的第一个目标是确定雌激素治疗在多大程度上改善卵巢功能不全的老年小鼠的肌球蛋白功能和肌肉力量。雌激素治疗将在雌激素缺乏的各种模型中进行评估，以便揭示雌二醇对肌球蛋白和肌肉功能的任何与年龄相关的不同影响。广泛的功能分析将包括随意的肌肉表现，活体小腿肌肉的最大力量，分离肌肉的收缩能力，以及肌球蛋白的分子结构-功能分析。这项应用的第二个目的是确定雌二醇是否对肌球蛋白和肌肉力量有益，独立于体力活动水平。雌激素对骨骼肌的直接作用是必须确定的，因为雌二醇的丢失和治疗是全身性的，因此，非肌肉组织受到影响，并可能通过间接机制影响肌肉。例如，啮齿动物的体力活动受到雌二醇状态的影响，并可能间接影响肌肉力量。这项应用的第三个目的是检验这样一种假设，即雌激素对肌球蛋白和肌肉功能的有益影响是由调控氧化应激相关基因的核雌激素受体介导的。要做到这一点，雌激素受体将被阻断，据预测，这种药物干预将否定雌激素对肌球蛋白和肌肉的所有有益影响。接下来，我们将探索一组与雌激素缺乏和雌激素充足的小鼠的氧化应激和抗氧化防御系统有关的基因。这背后的理论基础是，肌球蛋白对氧化很敏感，而且在非肌肉组织中，几个与氧化应激相关的基因受到雌激素的调节。在这些研究的结论中，我们将知道与年龄相关的雌二醇缺乏导致肌球蛋白功能下降导致肌肉力量下降的程度，以及雌二醇治疗是否通过基因组机制逆转这些下降。我们研究的长期目标是阐明与年龄和激素相关的骨骼肌功能丧失的总体机制，并利用这一知识设计出预防、逆转或至少减缓随年龄发生的虚弱进展的最佳策略。骨骼肌无力是一个重大的健康问题，因为它直接导致生活质量下降，特别是对老年妇女来说。公共卫生相关性：衰老导致肌肉无力，影响老年人的生活质量。在这项申请中描述的研究将确定雌激素治疗如何通过改善肌肉力量而使雌激素缺乏的女性受益。

DESCRIPTION (provided by applicant): The loss of skeletal muscle function occurs with age but the reason why there are differences in the rate and magnitude of loss between females and males is not clear. Losses in women are likely related to changes in ovarian hormones in addition to aging but mechanistic effects of these hormones on skeletal muscle have not been elucidated. The overall goal of the studies outlined in this application is to determine hormone-mediated mechanisms that contribute to muscle strength loss in aged females. Estradiol is the crucial ovarian hormone that affects the function of the key contractile protein, myosin, which in turn affects muscle strength in young adult female mice but estradiol's effects on muscle in aged female mice are unknown. Thus, the first aim of this application is to determine the extent to which estradiol treatment improves myosin function and muscle strength in ovarian-failed, aged mice. Estradiol treatment will be evaluated in various models of estradiol deficiency so that any age-related differential effects of estradiol on myosin and muscle functions will be revealed. Extensive functional analyses will include voluntary muscle performance, maximal in vivo lower-leg muscle strength, contractile capacity of isolated muscles, and molecular structure-function analyses of myosin. The second aim of this application is to determine if estradiol is beneficial to myosin and muscle strength independent of the physical activity level. The direct effects of estradiol on skeletal muscle are imperative to determine because the loss of and treatment with estradiol occurs systemically and as such, non-muscle tissue is affected and could influence muscle through indirect mechanisms. For example, physical activity of rodents is influenced by estradiol status and could indirectly impact muscle strength. The third aim of this application is to test the hypothesis that the beneficial effects of estradiol on myosin and muscle function are mediated by nuclear estrogen receptors, which regulate oxidative stress-related genes. To accomplish this, estrogen receptors will be blocked and it is predicted that this pharmacological intervention will negate all of estradiol's beneficial effects on myosin and muscle. Next, a panel of genes that are related to oxidative stress and antioxidant defense systems in estradiol-deficient and estradiol-replete mice will be probed. The rationale behind this is that myosin is susceptible to oxidation and that several oxidative stress-related genes are modulated by estradiol in non-muscle tissues. At the conclusion of these studies we will know the extent to which age-related estradiol deficiency causes a decline in muscle strength due to decrements in myosin function and whether estradiol treatment reverses these declines through genomic mechanisms. The long-term objective of our research is to elucidate the overall mechanisms underlying age- and hormone-related skeletal muscle functional losses and to utilize this knowledge to devise optimal strategies for preventing, reversing, or at least slowing the progression of weakness that occurs with age. Skeletal muscle weakness is a significant health concern because it directly contributes to a decreased qualit of life, particularly for older women. PUBLIC HEALTH RELEVANCE: Aging results in muscle weakness that impacts the quality of life of older adults. The research described in this application will determine how estradiol treatment can benefit estrogen-deficient females by improving muscle strength.