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

雌激素、年龄和活动对女性肌肉骨骼强度的相互作用

• 批准号: 7758235
• 负责人: DAWN A LOWE
• 金额: $ 30.12万
• 依托单位: UNIVERSITY OF MINNESOTA
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-02-01 至 2014-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7758235
• 关键词: Address; Affect; Age; Aging; Antioxidants; Contractile Proteins; Data; Elderly; Estradiol; Estrogen Nuclear Receptor; Estrogen Receptors; Estrogens; Experimental Designs; Female; Functional disorder; Genes; Genomics; Goals; Health; Hormonal; Hormones; Intervention; Knowledge; Leg; Life; Link; Mediating; Methodology; Modeling; Molecular Structure; Mus; Muscle; Muscle Weakness; Muscle function; Musculoskeletal; Myosin ATPase; Ovarian; Ovarian hormone; Oxidative Stress; Performance; Physical activity; Play; Quality of life; Research; Rodent; Rodent Model; Role; Skeletal Muscle; Solid; System; Testing; Woman; Work; age related; aged; base; functional loss; improved; in vivo; innovation; male; muscle aging; muscle strength; muscular system; older women; oxidation; prevent; public health relevance; senescence; young adult

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.

描述（由申请人提供）：骨骼肌功能的丧失是随着年龄的增长而发生的，但尚不清楚女性和男性之间损失的率和幅度差异。除衰老外，女性的损失可能与卵巢激素的变化有关，但是这些激素对骨骼肌的机械作用尚未阐明。本应用中概述的研究的总体目标是确定激素介导的机制，这些机制导致老年女性的肌肉力量损失。雌二醇是影响关键收缩蛋白肌球蛋白功能的至关重要的卵巢激素，进而影响年轻的成年雌性小鼠的肌肉力量，但雌二醇对老年雌性小鼠的肌肉的影响是未知的。因此，该应用的第一个目的是确定雌二醇治疗在多大程度上改善卵巢失败的老年小鼠的肌球蛋白功能和肌肉力量。雌二醇治疗将在各种雌二醇缺乏模型中进行评估，以便揭示雌二醇对雌二醇对肌球蛋白和肌肉功能的任何差异作用。广泛的功能分析将包括自愿性肌肉性能，最大的体内下腿肌强度，分离肌肉的收缩能力以及肌球蛋白的分子结构功能分析。该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于身体活动水平。雌二醇对骨骼肌的直接影响必须确定，因为雌二醇的丧失和治疗是系统地发生的，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，啮齿动物的体育活动受雌二醇状态的影响，可能会间接影响肌肉力量。该应用的第三个目的是检验以下假设：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。为此，将阻止雌激素受体，并预测该药理干预将抵消雌二醇对肌球蛋白和肌肉的所有有益作用。接下来，将探测与雌二醇缺陷型和雌二醇 - 复发小鼠中氧化应激和抗氧化剂防御系统有关的基因。其背后的理由是肌球蛋白易于氧化，并且在非肌肉组织中，雌二醇调节了几种与氧化应激相关的基因。在这些研究结束时，我们将知道与年龄相关的雌二醇缺乏在多大程度上导致肌球蛋白功能下降引起的肌肉力量下降，以及雌二醇治疗是否通过基因组机制逆转了这些下降。我们研究的长期目标是阐明与年龄和激素相关的骨骼肌肉功能损失的基本总体机制，并利用这些知识来制定最佳策略，以防止，逆转或至少减慢弱点的发展，而无力的发展则随着年龄的增长而发生。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，尤其是对于老年妇女。公共卫生相关性：衰老会导致肌肉无力影响老年人的生活质量。本应用中描述的研究将确定雌二醇治疗如何通过改善肌肉力量来使缺陷雌激素的女性受益。