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

描述（由申请人提供）：骨骼肌强度丧失是衰老的不良后果，可预测福尔斯和功能状态下降，导致老年人虚弱、残疾和丧失独立性。女性的骨骼肌还受到年龄的影响，因为随着更年期的开始，卵巢激素的产生减少。雌激素是关键的激素，因为女性的力量损失可以通过这种激素的治疗来预防或逆转。我们研究的长期目标是阐明年龄和雌二醇相关的骨骼肌功能丧失的机制，并利用这些知识来设计最佳策略，以抵消随着年龄的增长而发生的弱点。这是一个资助提案的竞争性更新提交，其中令人兴奋的发现和上一个资助期的许多出版物导致了本提案中概述的新假设。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;目标是确定老年女性力量损失的精确肌球蛋白机制，并阐明雌二醇如何影响肌肉力量的维持。具体来说，目标1将测试的假设，即衰老和雌二醇缺乏症影响肌球蛋白的结构功能，通过雌激素受体介导的磷酸化收缩蛋白。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，并从新定义的超松弛状态招募肌球蛋白，这可能对女性健康有更广泛的影响，因为肌球蛋白的超松弛状态会抑制肌肉的代谢率和潜在的全身代谢。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，肌肉损伤后的力量恢复不完全。目的2将检验以下假设：早期炎症的关键介质、最近发现对雌二醇有反应的特异性趋化因子/细胞因子及其受体显著影响损伤后力量的恢复。实现这两个目标将揭示雌二醇缺乏的老年女性肌无力的潜在分子机制。每个目标的实验方法本质上都是组合的，使用体外和体内策略以及独特的生物药理学-生理学方法来提供雌二醇如何有益于老年女性骨骼肌的新见解。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.