Mechanisms underlying local and systemic effects of massage

总结 骨骼肌质量的损失是与诸如癌症、艾滋病、糖尿病、充血性心力衰竭和衰老等疾病相关的常见症状。肌肉萎缩与疾病预后不良和生活质量下降有关，因此，在废用性萎缩期间保持肌肉大小和减少肌肉损失具有重要意义。肌肉的机械刺激，例如在阻力运动期间，诱导增加肌肉蛋白质含量和肌肉大小所需的蛋白质合成。我们发现，以按摩形式施加于骨骼肌的机械刺激是大鼠中有效的机械疗法，因为它导致蛋白质周转的转变，有利于再生和废用诱导的萎缩后的再生。目前还不清楚按摩是否对人类产生同样的积极影响，但如果阻力运动禁忌或不可行，则对骨骼肌和整体健康非常有益。除了对按摩大鼠肌肉的直接合成代谢作用外，我们还对大鼠和人类对侧非按摩肢体的同源肌肉表现出同样有益的反应。这一新的发现表明存在间接机制，可能对按摩肌肉以外的系统产生深远的影响。细胞外囊泡（EV）是从细胞释放的脂质膜结合囊泡，其具有调节释放它们的细胞的功能以及调节它们与之融合的细胞的功能的能力。因此，电动汽车可能是人类按摩对大脑和其他器官的影响的介质，这些影响有充分的记录但知之甚少，例如缓解疼痛，焦虑或抑郁或免疫力的变化。因此，该提案的目标是确定按摩对人体肌肉的合成代谢影响，并确定按摩释放的电动汽车是否是这种机械疗法对肌肉和其他器官产生有益影响的候选者。还将研究神经元活动的贡献。在目标1中，我们将解决以下假设：按摩作为一种机械疗法，通过将蛋白质生物合成转向anasthenia。我们将使用一种新型的按摩装置，通过单侧下肢悬吊对萎缩的肌肉施加机械负荷，并确定肌肉大小调节的机制。蛋白质合成将是主要结果。在探索性目标2中，我们将测试按摩通过EV或神经元活动的变化诱导交叉效应的假设。我们将测量来自目标1的人类受试者的血清中的EV及其miRNA货物，以及肌肉中EV生物发生的标志物。还将测量对侧肢体的肌肉激活。这项研究的结果不仅将表明机械疗法（如按摩）如何在废用期间减轻萎缩和增强合成代谢过程，而且还将确定电动汽车是否是按摩整体健康益处的候选机制。该应用程序直接解决了国家补充和综合健康中心以下计划公告中规定的目标：PA-18-322健康：关于身心方法的基础科学研究（R21）。

SUMMARY The loss of skeletal muscle mass is a common symptom associated with diseases such as cancer, AIDS, diabetes, congestive heart failure, and with aging. Muscle atrophy is associated with poor disease prognosis and decreased quality of life and therefore, maintaining muscle size and reducing the loss of muscle during disuse atrophy is of vital significance. Mechanical stimulation of muscle, such as during resistance exercise, induces protein synthesis needed to increase muscle protein content and muscle size. We showed that mechanical stimulation applied to skeletal muscle in the form of massage is an effective mechanotherapy in rats, since it leads to a shift in protein turnover favoring anabolism and enhanced regrowth after disuse-induced atrophy. Whether the same positive effect of massage occurs in humans is currently unknown, but would be extremely beneficial for skeletal muscle and overall health in case where resistance exercise is contraindicated or not feasible. In addition to the direct anabolic effects on the massaged rat muscle, we showed an equally beneficial response on the homologous muscle in the contralateral non-massaged limb of rats and humans. This novel finding indicated the existence of indirect mechanisms that could have profound systemic effects beyond the massaged muscle. Extracellular vesicles (EVs) are lipid membrane-bound vesicles released from cells with the ability to modulate function of cells from which they are released, as well as in cells with which they fuse. As such EVs are likely mediators of the well-documented but poorly-understood effects of massage in humans on the brain and other organs, such as relief of pain, anxiety or depression or changes in immunity. Therefore, the goal of this proposal is to determine anabolic effects of massage in human muscle, and to identify whether EVs released with massage are candidates for beneficial effects of this mechanotherapy on muscle as well as other organs. The contribution of neuronal activity will also be investigated. In Aim 1 we will address the following hypothesis: Massage acts as a mechanotherapy by shifting protein biogenesis towards anabolism. Using a novel massage device we will apply mechanical load to muscle undergoing atrophy through unilateral lower limb suspension and mechanisms underlying muscle size regulation determined. Protein synthesis will be the primary outcome. In the exploratory Aim 2 we will test the hypothesis that massage induces cross-over effects through changes in EVs or neuronal activity. We will measure EVs and their miRNA cargo in the serum, and markers of EV biogenesis in muscle of human subjects from Aim 1. Muscle activation in the contralateral limb will also be measured. Results from this study will indicate not only how mechanotherapy, such as massage, can attenuate atrophy and enhance anabolic processes during disuse, but also determine whether EVs are a candidate mechanism for the overall health benefits of massage. This application directly addresses the goals set out in the following program announcement from the National Center for Complementary and Integrative Health: PA-18-322 Health: Fundamental Science Research on Mind and Body Approaches (R21).