Interaction 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: 9917677
• 负责人: DAWN A LOWE
• 金额: $ 47.31万
• 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 2024-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9917677
• 关键词: Actins; Address; Adult; Affect; Age; Aging; Biochemical; Biological; Biology; Biophysics; Cell Culture Techniques; Cells; Chronic; Complement; Contractile Proteins; Cytometry; Estradiol; Estrogen Receptor alpha; Estrogen Receptors; Estrogens; Face; Female; Funding; Generations; Goals; Gonadal Steroid Hormones; Health; Impairment; In Vitro; Inflammation; Inflammatory; Inflammatory Response; Injury; Knowledge; Lead; Leukocytes; Life; Literature; Measurement; Measures; Mediating; Meta-Analysis; Molecular; Movement; Mus; Muscle; Muscle function; Muscular Atrophy; Musculoskeletal; Myosin ATPase; Operative Surgical Procedures; Ovarian; Ovarian hormone; Ovary; Pharmacology; Phosphorylation; Phosphotransferases; Physiological; Production; Publications; Quality of life; Receptor Signaling; Recovery; Relaxation; Research; Role; Skeletal Muscle; Solid; Techniques; Testing; Therapeutic; Tissues; Woman; aged; aging population; base; chemokine; clinically relevant; cytokine; disability; estrogen receptor gamma; estrogenic; estrophilin; female sex hormone; frailty; hormone deficiency; improved; in vivo; injured; innovation; muscle aging; muscle strength; neutrophil; novel; phosphoproteomics; pre-clinical; pre-clinical research; preclinical study; protein function; reduced muscle strength; repaired; reproductive; response; senescence; sex; skeletal muscle weakness; systematic review

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.

年龄引起的强度损失Dynapenia在女性中由于雌二醇（E2）缺乏而自然而然地强调 随着衰老而发生。该项目的总体目标是确定细胞和分子 E2缺乏症的机制使肌肉和肌球蛋白收缩功能以及E2如何 提高衰老女性的力量。这是一项资助的提案的竞争性更新提交 继续产生令人兴奋的发现和众多出版物。以前的资金结果 时期导致了该提议中概述的新颖假设。 AIM 1检验了E2的假设 缺乏导致因收缩蛋白磷酸化损害而导致的肌肉力量丧失 在放松期间，会损害产生力以及影响肌球蛋白超放松状态。此外，它 预测，用物理水平的E2治疗通过激活α雌激素来挽救强度 受体（ERα）和G蛋白ER（GPER）以及关键激酶的下游激活。创新的体内 实验方法和当代磷蛋白质组学技术，结合了E2的操纵 在身体，手术和遗传上，将使用雌激素机制作用 关于衰老的肌肉。骨骼肌在整个生命和衰老中忍受重复损伤以及E2缺乏症 损害这种伤害后的力量的恢复。在AIM 2中，对系统的系统评价和荟萃分析 文献与卵巢型成人和卵巢感知中E2处理的实验测试配对，年龄 小鼠将解决以下假设：从伤害中恢复强度所必需的肌肉感染是 随着E2的身体水平增强，但与超生理学水平钝化。 AIM 2还测试 假设E2缺乏会破坏受伤的肌肉中嗜中性粒细胞的功能，并将利用最先进的 质量细胞仪（Cytof）确定受伤肌肉中其他炎症细胞的E2反应性， 鉴定那些释放E2敏感趋化因子/细胞因子的细胞。这些目标的完成将 最终对我们对骨骼肌衰老的知识做出了重大贡献，尤其是在女性中。 具体而言，结果将提供有关临床上有关雌激素治疗的信息。 生殖时机的目的是了解E2如何最有效地保持肌肉力量和 衰老女性的运动质量。