Interaction of estrogen, age, and activity on musculoskeletal strength in females

年龄导致的力量丧失，月经迟缓，在女性中由于雌激素(E_2)缺乏而加剧。 随着年龄的增长而发生。这个项目的总体目标仍然是确定细胞和分子 雌激素缺乏扰乱肌肉和肌球蛋白收缩功能的机制及其机制 增强老年女性的力量。这是一份受资助提案的竞争性续订申请， 继续产生令人兴奋的发现和无数的出版物。前一次资助的结果 时期导致了这一提议中概述的新奇假设。AIM 1测试了E2的假设 由于收缩蛋白的磷酸化受损，缺乏导致肌肉力量的丧失 影响肌球蛋白在松弛过程中的超松弛状态，影响力量的产生。此外，它还 据预测，用生理水平的E2治疗可以通过激活α雌激素来挽救力量 受体(ER-α)和G蛋白-ER(GPER)及其下游关键蛋白的激活。体内创新 实验方法和当代磷酸蛋白质组学技术，结合对E2的操纵 雌激素受体在药理学、外科和遗传学上将被用于推断雌激素的作用机制。 对衰老的肌肉。骨骼肌在整个生命和衰老过程中承受着反复的损伤，以及E2缺乏 有损于这种损伤后力量的恢复。在目标2中，系统回顾和荟萃分析了 对卵巢切除的成人和卵巢衰老的老年患者进行雌激素治疗的文献和实验测试 小鼠将提出这样一种假设，即肌肉炎症是从损伤中恢复力量所必需的 随着生理水平的E2而增强，但随着超生理水平的降低而减弱。AIM 2还测试了 假设雌激素缺乏扰乱受损肌肉中的中性粒细胞功能，并将利用最新技术 用细胞质谱仪(CyTOF)测定损伤肌肉中其他炎性细胞的E2反应性。 也识别那些释放对E2敏感的趋化因子/细胞因子的细胞。完成这些目标将 最终对我们对骨骼肌衰老的认识做出了实质性的贡献，特别是在女性身上。 具体地说，结果将提供有关雌激素治疗的临床相关信息，而不是 生殖组织，目标是了解E2如何最有效地维持肌肉力量和 老年女性的运动质量。

Age-induced strength loss, dynapenia, is accentuated in females due to estradiol (E2) deficiency that naturally occurs with aging. The overall goal of this project remains on determining the cellular and molecular mechanisms through which E2 deficiency perturbs muscle and myosin contractile functions and how E2 improves strength in aging females. This is a competitive renewal submission of a funded proposal that continues to produce exciting discoveries and numerous publications. Results from the previous funding periods have led to the novel hypotheses outlined in this proposal. Aim 1 tests the hypothesis that E2 deficiency causes loss of muscle strength due to compromised phosphorylation of contractile proteins impairing force generation as well as affecting the myosin super relaxed state during relaxation. Furthermore, it is predicted that treatment with physiological levels of E2 rescues strength through activation of the α estrogen receptor (ERα) and the G protein ER (GPER) and downstream activation of key kinases. Innovative in vivo experimental approaches and contemporary phosphoproteomics techniques, combined with manipulation of E2 and ERs pharmacologically, surgically, and genetically will be used to deduce estrogenic mechanisms acting on aging muscle. Skeletal muscle endures repetitive injury throughout life and aging as well as E2 deficiency impair the recovery of strength following such injury. In Aim 2, a systematic review and meta-analysis of the literature paired with experimental testing of E2 treatment in ovariectomized adult and ovarian-senescent, aged mice will address the hypothesis that muscle inflammation, necessary for recovery of strength from injury, is enhanced with physiological levels of E2 but blunted with supraphysiological levels. Aim 2 also tests the hypothesis that E2 deficiency disrupts neutrophil functions in injured muscle, and will utilize state-of-the-art mass cytometry (CyTOF) to determine E2 responsiveness of other inflammatory cells in injured muscle, identifying those cells that release E2-sensitive chemokines/cytokines as well. Completion of these aims will culminate in substantial contributions to our knowledge of aging skeletal muscle, especially in females. Specifically, results will provide clinically-relevant information about estrogenic treatments beyond those for reproductive tissues with the goal of understanding how E2 can most effectively maintain muscle strength and movement quality in aging women.