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

描述（由申请人提供）：骨骼肌功能丧失随年龄增长而发生，但女性和男性之间丧失速率和程度存在差异的原因尚不清楚。女性的损失可能与卵巢激素的变化以及衰老有关，但这些激素对骨骼肌的机械作用尚未阐明。本申请中概述的研究的总体目标是确定导致老年女性肌肉力量损失的肌肉介导的机制。雌二醇是一种重要的卵巢激素，它影响关键的收缩蛋白肌球蛋白的功能，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，本申请的第一个目的是确定雌二醇治疗在卵巢衰竭的老年小鼠中改善肌球蛋白功能和肌肉力量的程度。将在各种雌二醇缺乏模型中评价雌二醇治疗，以便揭示雌二醇对肌球蛋白和肌肉功能的任何年龄相关差异效应。广泛的功能分析将包括随意肌肉的性能，最大的在体内小腿肌肉力量，收缩能力的孤立的肌肉，和肌球蛋白的分子结构-功能分析。本申请的第二个目的是确定雌二醇是否有益于肌球蛋白和肌肉力量，而与身体活动水平无关。必须确定雌二醇对骨骼肌的直接影响，因为雌二醇的损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，啮齿动物的身体活动受雌二醇状态的影响，并可能间接影响肌肉力量。本申请的第三个目的是检验雌二醇对肌球蛋白和肌肉功能的有益作用是由调节氧化应激相关基因的核雌激素受体介导的假设。为了实现这一点，雌激素受体将被阻断，据预测，这种药理学干预将否定雌二醇对肌球蛋白和肌肉的所有有益作用。接下来，一组与雌二醇缺乏和雌二醇充足小鼠的氧化应激和抗氧化防御系统相关的基因将被探测。这背后的基本原理是，肌球蛋白易受氧化，并且在非肌肉组织中，几种氧化应激相关基因受到雌二醇的调节。在这些研究的结论，我们将知道在何种程度上与年龄相关的雌二醇缺乏导致肌肉力量下降，由于在肌球蛋白功能的递减和雌二醇治疗是否逆转这些下降通过基因组机制。我们研究的长期目标是阐明与年龄和衰老相关的骨骼肌功能丧失的总体机制，并利用这些知识制定预防、逆转或至少减缓随年龄增长而发生的虚弱进展的最佳策略。骨骼肌无力是一个重要的健康问题，因为它直接导致生活质量下降，特别是老年妇女。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。本申请中描述的研究将确定雌二醇治疗如何通过改善肌肉力量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.