Estrogen Effects on Atrophic Skeletal Muscle

描述（由申请人提供）：在物理康复环境中，女性通常表现出比男性更少的功能恢复。雌激素（E2）缺乏可能导致性别差异，因为低E2水平与瘦肌肉量减少有关。在每年接受手术后或康复治疗的200多万女性中，大约有一半的人由于自然绝经、手术绝经和正常的激素节律被疾病或创伤打乱而“雌激素缺乏”。这个转化研究项目的总体目标是使用动物模型来确定外源性E2是否应该被视为E2缺乏女性标准物理康复的辅助手段。先前的动物研究表明，卵巢切除术（OVX）后缺乏循环E2会损害实验室诱导的萎缩骨骼肌的恢复。OVX大鼠萎缩肌肉再生失败与启动蛋白质合成失败有关。相比之下，给予E2激素替代疗法（HRT）的肌肉萎缩E2缺乏大鼠在一周内显示萎缩肌肉几乎完全再生。E2 HRT的肌肉再生与肌肉蛋白合成的Akt/mTOR通路的激活有关。此外，E2 HRT恢复肌纤维横截面积。拟议的项目将阐明E2缺乏雌性大鼠萎缩骨骼肌再生失败的相关机制。我们将对接受短期E2 HRT和标准物理康复锻炼的E2缺乏大鼠进行骨骼肌再生实验。我们还将检查肌肉再生的组成部分（例如，横截面积）。具体目的是：1)确定E2缺乏大鼠由E2 HRT或康复运动独立产生的萎缩骨骼肌再生的程度。2)确定E2 HRT联合康复运动是否能增强E2缺乏大鼠萎缩性骨骼肌再生的程度。3)利用雌激素受体（ER）敲除小鼠和ER特异性配体，确定E2对萎缩肌再生的作用是否通过ER1或ER2受体介导。对E2 HRT安全性的担忧迫使研究一种雌激素受体特异性化合物，该化合物将被证明有效且无不良副作用。拟议的研究将为确定短期雌激素（E2）治疗应被视为雌激素缺乏妇女标准物理康复护理的辅助手段的程度奠定基础。公共卫生相关性：大约1/2的成年女性人口可能由于绝经、手术、创伤或疾病而被认为雌激素缺乏。雌激素缺乏与长时间卧床休息后瘦肌肉量减少和肌肉再生受损有关。短期雌激素激素替代疗法可以为康复运动方案提供有价值的补充，但需要更多关于雌激素在骨骼肌中的作用和机制的信息。

DESCRIPTION (provided by applicant): In the physical rehabilitation setting, women typically demonstrate lesser return to function than men. Estrogen (E2) deficiency might contribute to the gender discrepancy, as low E2 levels have been linked to a decrease in lean muscle mass. Of the more than two million women receiving post-operative or rehabilitation care each year, approximately 1/2 of them are "estrogen-deficient" due to natural menopause, surgical menopause, and normal hormonal rhythms disrupted by illness or trauma. The overall goal of this translational research project is to use animal models to determine if exogenous E2 should be considered as an adjunct to standard physical rehabilitation for E2 deficient women. Prior studies in animals have demonstrated that a lack of circulating E2 (subsequent to ovariectomy (OVX)) impairs recovery of laboratory-induced atrophic skeletal muscle. Failure to regrow atrophied muscles in OVX rats was associated with failure to initiate protein synthesis. In contrast, E2 deficient rats with muscle atrophy that were given E2 hormone replacement therapy (HRT) demonstrated nearly complete regrowth of atrophied muscle within a week. Muscle regrowth with E2 HRT is associated with activation of the Akt/mTOR pathway of muscle protein synthesis. Moreover, E2 HRT restored myofiber cross-sectional area. The proposed project will elucidate mechanisms associated with the failure to regrow atrophied skeletal muscle in the E2 deficient female rat. We will conduct experiments that examine skeletal muscle regrowth for the E2-deficient rats receiving short-term E2 HRT and standard physical rehabilitation exercise. We will also examine the components of muscle regrowth (e.g., cross-sectional area). The specific aims are to: 1) determine the extent of atrophic skeletal muscle regrowth produced independently by E2 HRT or rehabilitation exercise in E2 deficient rats. 2) Determine if E2 HRT combined with rehabilitation exercise can augment the extent of atrophic skeletal muscle regrowth in E2 deficient rats. 3) Use estrogen receptor (ER) knock-out mice and ER-specific ligands to determine if the E2 effect on atrophic muscle regrowth is mediated through the ER1 or ER2 receptor. Concerns about the safety of E2 HRT compel investigation of an ER specific compound that will prove effective without undesirable side-effects. The proposed studies will lay the groundwork for determining the extent to which short-term estrogen (E2) therapy should be considered as an adjunct to standard physical rehabilitation care for estrogen deficient women. PUBLIC HEALTH RELEVANCE: Approximately 1/2 of the adult female population may be considered estrogen deficient due to menopause, surgery, trauma or illness. Estrogen deficiency has been linked to a decrease in lean muscle mass and impaired muscle regrowth following extended bed rest. Short-term estrogen hormone replacement therapy could provide a valuable addition to rehabilitation exercise protocols, but more information about the role and mechanism of estrogen effectiveness in skeletal muscle is needed.