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

描述（由申请人提供）：骨骼肌力量的丧失是衰老的不良后果，预示着跌倒和功能状态下降，导致老年人虚弱、残疾和丧失独立性。女性的骨骼肌也受到年龄的影响，因为卵巢激素的分泌随着更年期的开始而减少。雌二醇是关键的激素，因为用这种激素治疗可以防止或逆转女性的力量损失。我们研究的长期目标是阐明与年龄和雌二醇相关的骨骼肌功能丧失的机制，并利用这些知识设计出最佳策略来抵消随着年龄增长而出现的虚弱。这是一个竞争性的更新提交的资助提案，其中令人兴奋的发现和大量的出版物从上一个资助时期导致了新的假设，在本提案中概述。该项目的总体重点仍然是雌二醇如何影响老年女性的骨骼肌力量；目的是确定基于肌球蛋白的老年女性力量损失的精确机制，并阐明雌二醇如何影响肌肉力量的维持。具体来说，Aim 1将验证衰老和雌二醇缺乏通过雌激素受体介导的收缩蛋白磷酸化影响肌球蛋白结构功能的假设。我们建议雌二醇治疗增加关键收缩蛋白的磷酸化，如调节轻链，以增强力的产生，并从新定义的超放松状态中招募肌凝蛋白，这可能对女性健康有更广泛的影响，因为肌凝蛋白的超放松状态会降低肌肉的代谢率，甚至可能降低全身代谢。第二个目标的重点是维持女性的力量，这需要肌肉从一生中持续的反复受伤中恢复过来。由于雌二醇缺乏，肌肉损伤后力量的恢复是不完全的。目的2将验证早期炎症的关键介质，特异性趋化因子/细胞因子及其受体最近发现对雌二醇有反应，显著影响损伤后力量恢复的假设。完成这两个目标将揭示雌二醇缺乏的老年女性肌肉无力的潜在分子机制。每个目标的实验方法本质上是组合的，使用体外和体内策略以及独特的生物物理生理学方法，为雌二醇如何有益于老年女性骨骼肌提供新的见解。这项工作继续挑战雄激素是肌肉力量唯一重要的性激素的概念。

DESCRIPTION (provided by applicant): The loss of skeletal muscle strength is an undesirable consequence of aging and is predictive of falls and declining functional status leading to frailty, disability, and loss of independence for aged individuals. Skeletal muscle of females is additionally affected by age due to the reduction of ovarian hormone production with the onset of menopause. Estradiol is the key hormone because strength loss in females is prevented or reversed by treatment with this hormone. The long-term objective of our research is to elucidate the mechanisms underlying age- and estradiol-related skeletal muscle functional losses and to utilize this knowledge to devise optimal strategies for offsetting weakness that occurs with age. This is a competitive renewal submission of a funded proposal whereby exciting discoveries and numerous publications from the previous funding period have led to novel hypotheses that are outlined in this proposal. The overall focus of the project remains to be on how estradiol impacts skeletal muscle strength in aged females; the goals are to determine precise myosin- based mechanisms of strength loss in aging females and to elucidate how estradiol impacts the maintenance of muscle strength. Specifically, Aim 1 will test the hypothesis that aging and estradiol-deficiency affect the structure-function of myosin through estrogen receptor-mediated phosphorylation of contractile proteins. We propose that estradiol treatment increases phosphorylation of key contractile proteins such as the regulatory light chain to enhance force generation and to recruit myosin from a newly defined super-relaxed state, which possibly has wider implications in women's health because the super-relaxed state of myosin depresses metabolic rate of muscle and potentially whole body metabolism. The focus of the second aim is on maintenance of strength in females, which requires that muscle recover from the repeated bouts of injury that it sustains throughout life. As a consequence of estradiol deficiency, recovery of strength following muscle injury is incomplete. Aim 2 will test the hypothesis that key mediators of early inflammation, specific chemokines/cytokines and their receptors recently found to be responsive to estradiol, significantly impact recovery of strength post-injury. Accomplishing these two aims will reveal underlying molecular mechanisms of muscle weakness in estradiol-deficient, aged females. Experimental approaches in each aim are combinatorial in nature, using in vitro and in vivo strategies and unique biophysical-physiological approaches to provide novel insights into how estradiol is beneficial for skeletal muscle of aged females. This work continues to challenge the concept that androgens are the only important sex hormones for muscle strength.