Sex specific adaptations to muscle unloading

描述(由申请人提供)：越来越明显的是，神经肌肉系统--与其他重要的生理系统一样--在结构(纤维大小和纤维类型组成)和功能(生物能量途径和抗疲劳能力)方面表现出性别二态特征。最近，有证据表明，男性和女性对肌肉卸载的适应也不同。也就是说，女性经历的卸货导致的肌肉功能下降幅度比男性大得多。到目前为止，证据表明，女性对肌肉卸载的更高敏感性与肌肉神经激活(即肌电活动)的明显减弱有关，而与肌肉萎缩的性别差异无关。这项拟议项目的总体目标是确定肌肉卸载导致的肌肉神经活动的性别特异性下降的性质和部位。这将通过比较卸载引起的功能性神经肌肉传递效率、神经肌肉连接形态、肌纤维轮廓(纤维类型和大小)以及突触功能和结构的两个重要调节分子NCAM和synaptopagmin的表达而得到解决。该项目的第一个目标将专注于检测年轻成年男性与女性在肌肉卸载时的神经肌肉重塑。第二个目标将研究年龄对特定性别的卸货适应的影响；这一点至关重要，因为老年人更有可能遭受意外摔倒和医疗程序导致肌肉卸货。在第三个目标中，将评估性二型性类固醇内分泌环境对性特异性适应卸货的影响。本实验以雄性和雌性大鼠为实验对象(Aim 1为青年大鼠，Aim 2为老年大鼠，Aim 3为去性腺青年大鼠)，并采用后肢悬吊卸载模型。这里收集的数据将为新报道的和临床上重要的发现提供新的见解，即男性和女性的神经肌肉系统因肌肉卸载而遭受不同程度的障碍。通过了解这种性别特异性重塑的性质，就有可能在各个年龄段的男性和女性频繁发生肌肉卸载的情况下，优化康复策略。 公共卫生相关性：由于医疗程序和意外跌倒，每年有数以千计的美国人--包括年轻人和老年人--遭受肌肉卸载，导致神经肌肉功能受损。最近的研究结果表明，性别影响卸货会导致神经肌肉功能的下降。为了优化康复策略，恢复年轻和老年男性和女性，了解这种性别特有的重塑的位置和因素是至关重要的。

DESCRIPTION (provided by applicant): Increasingly it has become apparent that the neuromuscular system - like other vital physiological systems - displays sexually dimorphic characteristics in structure (fiber size and fiber type composition) and function (bioenergetic pathways and resistance to fatigue). More recently, evidence has shown that men and women also experience different adaptations to muscle unloading. That is, women experience significantly greater unloading induced declines in muscle function than men. To date, the evidence suggests that the greater sensitivity of women to muscle unloading is related to more pronounced decrements in neural activation of muscle (i.e. EMG activity) and not to sex specific differences in muscle atrophy. The overall goal of this proposed project is to determine the nature and locus of sex specific declines in neural activation of muscle brought about by muscle unloading. This will be approached by comparing unloading induced diminutions in functional neuromuscular transmission efficacy, neuromuscular junction morphology, myofiber profiles (fiber type and size) and the expression of NCAM and Synaptotagmin, two important regulatory molecules of synaptic function and structure. The project's 1st Aim will focus on examining neuromuscular remodeling in response to muscle unloading in young adult males vs. females. The 2nd Aim will examine the effect of aging on sex specific adaptations to unloading; this is vital since the aged are far more likely to suffer accidental falls and medical procedures resulting in muscle unloading. In the 3rd Aim, the causative effect of sexually dimorphic sex steroid endocrine milieus on sex specific adaptations to unloading will be evaluated. In the experiments proposed here, male and female rats will be used as subjects for the project (young adults for Aim 1, aged for Aim 2, gonadectomized young adults for Aim 3), and the hind limb suspension model of unloading will be employed. The data gathered here will provide novel insight into the newly reported and clinically important finding that male and female neuromuscular systems suffer different degrees of disturbance due to muscle unloading. By understanding the nature of this sex specific remodeling, it will be possible to optimize rehabilitative strategies following the condition of muscle unloading that occurs all too frequently in men and women of all ages. PUBLIC HEALTH RELEVANCE: As a result of medical procedures and accidental falls thousands of Americans - both young and old - are subjected to muscle unloading each year eliciting impairments in neuromuscular function. Recent findings indicate that gender influences unloading induced declines in neuromuscular function. Understanding the locus and factors accounting for this gender specific remodeling is essential in order to optimize rehabilitative strategies for recovering young and aged men and women.