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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

基本信息

批准号：
10561618
负责人：
DAWN A LOWE
金额：
$ 43.96万
依托单位：
UNIVERSITY OF MINNESOTA
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-02-01 至 2025-01-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10561618
关键词：
Actins Adult Affect Age Aging Biochemical Biological Biology Biophysics Cell Culture Techniques Cell Separation Cells Chronic Complement Contractile Proteins Cytometry Estradiol Estradiol Receptors Estrogen Receptor alpha Estrogen Receptors Estrogen deficiency Estrogens Face Female Funding GTP-Binding Proteins Generations Goals Gonadal Steroid Hormones Health Impairment In Vitro Inflammation Inflammatory Inflammatory Response Injury Knowledge Leukocytes Life Literature Measurement Measures Mediating Meta-Analysis Molecular Molecular Mechanisms of Action Movement Mus Muscle Muscle function Muscular Atrophy Musculoskeletal Myosin ATPase Operative Surgical Procedures Ovarian Ovarian hormone Ovary Phosphorylation Phosphotransferases Physiological Prediction of Response to Therapy Production Publications Quality of life Receptor Signaling Recovery Relaxation Research Role Skeletal Muscle Solid Techniques Testing Therapeutic Tissues Woman aged aging population chemokine clinically relevant cytokine disability estrogenic estrophilin frailty hormone deficiency human old age (65+)improved in vivo injured innovation muscle aging muscle strength neutrophil novel pharmacologic phosphoproteomics pre-clinical pre-clinical research preclinical study protein function reduced muscle strength repaired reproductive response senescence sex skeletal muscle weakness systematic review

项目摘要

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.

由于雌二醇 (E2) 缺乏，女性中年龄引起的体力丧失、缺乏缺乏症会更加严重。随着衰老而发生。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 的作用提高老年女性的力量。这是一项资助提案的竞争性更新提交，继续产生令人兴奋的发现和大量出版物。先前资助的结果不同时期导致了本提案中概述的新颖假设。目标 1 检验假设 E2 由于收缩蛋白磷酸化受损，缺乏会导致肌肉力量丧失损害力量的产生以及影响放松期间肌球蛋白的超放松状态。此外，它据预测，生理水平的 E2 治疗可通过激活 α 雌激素来恢复力量受体 (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 的操作 ER 将通过药理学、外科手术和遗传学来推断雌激素作用机制关于老化的肌肉。骨骼肌在整个生命和衰老过程中都会遭受重复性损伤以及 E2 缺乏损害此类损伤后力量的恢复。在目标 2 中，对文献与 E2 治疗在卵巢切除成人和卵巢衰老老年人中的实验测试相结合老鼠将提出这样一个假设：肌肉炎症是从受伤中恢复力量所必需的， E2 的生理水平增强，但超生理水平减弱。目标 2 还测试了假设 E2 缺乏会破坏受伤肌肉中的中性粒细胞功能，并将利用最先进的技术质谱流式细胞仪 (CyTOF) 测定受伤肌肉中其他炎症细胞的 E2 反应性，识别那些释放 E2 敏感趋化因子/细胞因子的细胞。完成这些目标将最终对我们对衰老骨骼肌（尤其是女性骨骼肌）的认识做出了重大贡献。具体来说，结果将提供有关雌激素治疗的临床相关信息，超出了雌激素治疗的范围。生殖组织，目的是了解 E2 如何最有效地维持肌肉力量和老年女性的运动质量。

项目成果

期刊论文数量（42）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Phosphoproteomic profiling of skeletal muscle twitch torque potentiation in ovarian hormone deficient female mice.

卵巢激素缺乏雌性小鼠骨骼肌抽搐扭矩增强的磷酸化蛋白质组学分析。

DOI：
发表时间：
2022
期刊：
FASEB journal : official publication of the Federation of American Societies for Experimental Biology
影响因子：
0
作者：
Peyton,Mina;Yang,TzuYi;Higgins,LeeAnn;Parker,Laurie;Lowe,Dawn
通讯作者：
Lowe,Dawn

Estrogen regulates estrogen receptors and antioxidant gene expression in mouse skeletal muscle.

DOI：
10.1371/journal.pone.0010164
发表时间：
2010-04-13
期刊：
PloS one
影响因子：
3.7
作者：
Baltgalvis KA;Greising SM;Warren GL;Lowe DA
通讯作者：
Lowe DA

Tissue selective effects of bazedoxifene on the musculoskeletal system in female mice.

DOI：
10.1530/joe-20-0391
发表时间：
2021-03
期刊：
The Journal of endocrinology
影响因子：
0
作者：
Cabelka CA;Baumann CW;Lindsay A;Norton A;Blixt NC;Le G;Warren GL;Mansky KC;Novotny SA;Lowe DA
通讯作者：
Lowe DA

Age affects myosin relaxation states in skeletal muscle fibers of female but not male mice.