Myosin structure & strength alterations in aging females

描述(申请人提供)：随着年龄的增长，人和动物的肌肉会发生收缩功能障碍。最具破坏性的功能障碍之一是肌肉力量的丧失，这最终可能导致老年人残疾和丧失独立性。男性逐渐失去力量，但女性在绝经前后力量下降的速度更快。这种加速丢失的机制尚不清楚，但可能与卵巢激素变化有关。由于与年龄和激素相关的收缩功能障碍的时间进程和程度在雌性小鼠中没有定义，因此需要对力量进行纵向评估，这是该试验项目的第一个目标的重点。我们假设，在绝经期间和卵巢切除后，随着雌二醇水平的降低，力量将会下降。我们还假设，卵巢切除后补充雌二醇将逆转力量的丧失。第二个目标是确定雌二醇相关强度损失的分子机制。根据初步数据，这些分子机制的最初焦点将是收缩蛋白-肌球蛋白。需要检验的中心假设是，循环中的雌二醇减少会有害地改变肌球蛋白的结构和功能，从而导致力量下降。肌球蛋白的功能将在细胞和分子水平上进行评估，肌球蛋白的结构将通过特定部位的自旋标记和电子顺磁共振光谱来确定。我们研究的长期目标是阐明与年龄和激素相关的力量丧失的分子机制，并利用这一知识设计预防或逆转功能障碍的策略。

DESCRIPTION (provided by applicant): Contractile dysfunction occurs in muscles of humans and animals with age. One of the most devastating dysfunctions is the loss of muscle strength, which can ultimately lead to disability and a loss of independence for elderly individuals. The loss of strength occurs gradually in men, but in women there is an increased rate of strength decline around the time of menopause. The mechanisms underlying this accelerated loss are not known but may to be related to ovarian hormone changes. Because the time courses and extent of age- and hormone-related contractile dysfunctions are not defined in female mice, a longitudinal assessment of strength is needed and is the focus of the first aim of this pilot project. We hypothesize that strength will decline as estradiol levels are reduced during menopause and as a result of ovariectomy. We also hypothesize that estradiol replacement following ovariectomy will reverse the strength loss. The goal of the second aim is to determine molecular mechanisms underlying estradiol-related strength losses. Based on preliminary data, the initial focus of these molecular mechanisms will be on the contractile protein, myosin. The central hypothesis to be tested is that reduced circulating estradiol causes declines in strength by detrimentally altering myosin structure and function. Myosin function will be assessed at the cellular and molecular levels and myosin structure will be determined by site-specific spin labeling and electron paramagnetic resonance spectroscopy. The long-term objective of our research is to elucidate the molecular mechanisms underlying age- and hormone- related strength losses and utilize this knowledge to devise strategies to prevent or reverse the dysfunction.