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

由于雌二醇（E2）缺乏，雌性动物的肌肉力量丧失，即肌肉无力， 随着年龄的增长而发生。该项目的总体目标仍然是确定细胞和分子 E2缺乏扰乱肌肉和肌球蛋白收缩功能的机制，以及E2 提高老年女性的力量。这是一个有资金支持的提案的竞争性更新提交， 继续产生令人兴奋的发现和许多出版物。上一次资助的结果 这些时期的变化导致了本提案中概述的新假设。目的1检验E2 由于收缩蛋白的磷酸化受损，缺乏会导致肌肉力量丧失 削弱力的产生以及影响肌球蛋白在松弛过程中的超松弛状态。而且 据预测，用生理水平的E2治疗通过激活α雌激素来拯救力量， 受体（ERα）和G蛋白ER（GPER）以及关键激酶的下游激活。体内创新 实验方法和当代磷酸化蛋白质组学技术，结合E2 雌激素受体，手术和遗传将被用来推断雌激素机制， 关于衰老的肌肉骨骼肌在整个生命和衰老过程中承受重复性损伤以及E2缺乏 在这种损伤之后，损害力量的恢复。在目标2中，对 文献与E2治疗卵巢切除成人和卵巢衰老，老年人的实验测试配对 小鼠将解决这一假设，即肌肉炎症，从受伤中恢复力量所必需的， E2在生理水平时增强，在超生理水平时减弱。Aim 2还测试了 假设E2缺乏会破坏受损肌肉中的中性粒细胞功能，并将利用最先进的 质谱细胞术（CyTOF）以确定损伤肌肉中其他炎性细胞的E2反应性， 也鉴定释放E2敏感性趋化因子/细胞因子的那些细胞。实现这些目标将 最终为我们对骨骼肌衰老的认识做出了重大贡献，尤其是在女性中。 具体来说，研究结果将提供有关雌激素治疗的临床相关信息， 生殖组织，目的是了解E2如何最有效地维持肌肉力量， 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.