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-像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性）方面显示出性二态特征。最近，有证据表明，男性和女性对肌肉卸载的适应性也不同。也就是说，女性比男性经历显著更大的卸载引起的肌肉功能下降。迄今为止，证据表明，女性对肌肉卸载的更大敏感性与肌肉神经激活（即EMG活动）的更明显减少有关，而与肌肉萎缩的性别特异性差异无关。这个项目的总体目标是确定肌肉卸荷引起的肌肉神经激活的性别特异性下降的性质和位点。这将通过比较卸载引起的功能性神经肌肉传递功效、神经肌肉接头形态、肌纤维概况（纤维类型和大小）以及NCAM和突触结合蛋白（突触功能和结构的两种重要调节分子）的表达的减少来接近。该项目的第一个目标将集中在检查神经肌肉重塑响应肌肉卸载在年轻的成年男性与女性。第二个目标将研究衰老对性别特异性适应卸载的影响;这是至关重要的，因为老年人更有可能遭受意外福尔斯和导致肌肉卸载的医疗程序。在第三个目标中，将评估性二型性类固醇内分泌环境对性别特异性卸载适应的影响。在本文提出的实验中，雄性和雌性大鼠将用作该项目的受试者（目标1为年轻成年大鼠，目标2为老年大鼠，目标3为性腺切除的年轻成年大鼠），并将采用后肢悬吊卸载模型。这里收集的数据将提供新的见解，新报告的和临床上重要的发现，男性和女性的神经肌肉系统遭受不同程度的干扰，由于肌肉卸载。通过了解这种性别特异性重塑的性质，将有可能在所有年龄段的男性和女性中经常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的福尔斯跌倒，每年有成千上万的美国人--无论年轻人还是老年人--遭受肌肉卸载，从而引起神经肌肉功能的损伤。最近的研究结果表明，性别影响卸载引起的神经肌肉功能下降。了解的轨迹和因素占这种性别特异性重塑是必不可少的，以优化康复策略，恢复年轻和老年男性和女性。

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.