Mechanisms underlying anabolic effects of cyclic compressive loading in muscle

骨骼肌质量的损失是许多疾病状态中残疾的主要原因，也是导致残疾的主要原因。 是老年人死亡率的预测因子，也是老年人丧失独立性的主要因素。我们建议按摩是 一种新的干预措施，以减轻急性肌肉萎缩或帮助患者肌肉损失后的再生， 无法进行锻炼。按摩是一种临床上广泛用于缓解疼痛的手动治疗方式 作为免疫反应的调节剂;然而，很少有研究涉及实际的 按摩的有益效果的基本机制，主要是因为缺乏一致性， 外加载荷使用创新的循环压缩载荷（CCL）装置，模拟小型啮齿动物， 按摩与一个明确的负荷，我们表明，CCL提高蛋白质合成时，管理期间， 废用或萎缩后恢复，并增强成年大鼠按摩肢体的再生反应， 而在未受干扰的或年老的大鼠中没有观察到效果。令人惊讶的是，我们还发现了积极的再生反应， 在对侧，没有按摩的肢体上我们认为，蛋白质的合成是通过 机械敏感性合成代谢途径，如粘着斑复合物，包括粘着斑激酶 (FAK)和整合素连接的激酶（ILK）在按摩的肢体和生长的影响，在非按摩 肢体是由神经元交叉效应或系统介导的机制介导的。这些初步 数据导致以下假设：按摩，在CCL的形式，对肌肉产生合成代谢作用 直接通过机械敏感通路，以及间接通过神经或全身介导 机制，以提高肌肉的大小在扰动的增长状态。我们将在大鼠中使用CCL来研究 使用生长扰动的肌肉生长反应，即废用性萎缩和萎缩后的再生。目标1 我们将建立老年人肌肉对CCL的生长反应减弱的机制， 成年大鼠和测试的假设，从老年大鼠的肌肉表现出衰减反应CCL，因为 更坚硬的细胞外基质和蛋白质合成池的变化。在目标2中，机械敏感性 将研究CCL后成年大鼠骨骼肌中负责生长反应的途径 特别关注FAK和卫星细胞的作用。在目标3中，我们将检验以下假设： CCL后对侧非按摩肢体蛋白质合成和肌肉大小的增加是由于 感觉反馈调节的交叉效应，但也将研究系统介导的作用，如 细胞因子和外泌体介导的miRNA转移。这些研究的结果将表明， 按摩是一种可行的干预措施，可以防止肌肉质量在废用期间的损失或促进肌肉的再生。 肌肉萎缩后，同时确定有益的合成代谢作用的潜在机制。

The loss of skeletal muscle mass is a main contributor to disability in numerous disease states and is also a predictor of mortality and a major factor in the loss of independence in the elderly. We propose that massage is a novel intervention to attenuate acute muscle atrophy or aid with regrowth after muscle loss in patients who are unable to perform exercise. Massage is a manual therapy modality extensively used clinically for pain relief and as a modulator of immune responses; however, very few investigations have addressed the actual underlying mechanisms of the beneficial effects of massage, mainly because of the lack of consistency in the applied load. Using an innovative cyclic compressive loading (CCL) device for small rodents, mimicking massage with a well-defined load, we showed that CCL elevated protein synthesis when administered during disuse or recovery after atrophy, and enhanced the regrowth response in adult rats in the massaged limb, while no effect was seen in unperturbed or aged rats. Surprisingly, we also found a positive regrowth response in the contralateral, non-massaged limb. We suggest that protein synthesis is elevated through mechanosensitive anabolic pathways, such as the focal adhesion complexes including focal adhesion kinase (FAK) and integrin-linked kinase (ILK) in the massaged limb and that the growth effect in the non-massaged limb is mediated by a neuronal cross-over effect or by systemically-mediated mechanisms. These preliminary data led to following hypothesis: Massage, in the form of CCL, exerts an anabolic effect on muscle directly through mechanosensitive pathways, as well as indirectly by neurally or systemically mediated mechanisms, to enhance muscle size in perturbed growth states. We will use CCL in rats to study the muscle growth response using growth perturbations, i.e. disuse atrophy and regrowth after atrophy. In Aim 1 we will establish mechanisms for the attenuated growth response to CCL in muscles from aged compared to adult rats and test the hypothesis that muscles from aged rats show an attenuated response to CCL because of a stiffer extracellular matrix and a change in the pool of proteins synthesized. In Aim 2 the mechanosensitive pathways responsible for the growth response in skeletal muscle from adult rats after CCL will be investigated with particular attention to FAK and the role of satellite cells. In Aim 3 we will test the hypothesis that the increase in protein synthesis and muscle size in the contralateral non-massaged limb after CCL is due to a sensory feedback-regulated cross-over effect, but will also investigate systemic-mediated actions, such as cytokines and exosome-mediated transfer of miRNAs. Results from these studies will indicate whether massage is a viable intervention for preventing the loss of muscle mass during disuse or promoting regrowth of muscle after atrophy while determining the underlying mechanisms for the beneficial anabolic effects.