Cyclic compressive loading to negate atrophy and impaired regrowth in aged muscle

描述（由申请人提供）：衰老与不活动后恢复肌肉质量和力量的能力下降有关，老年人经常受到这种影响，导致虚弱和功能依赖。骨骼肌不仅对力量的发展至关重要，而且也是主要的蛋白质储存库，并且是移动性、易受伤性和死亡率的重要预测因子。因此，设计干预措施以减轻废用期间肌肉尺寸的减小并帮助萎缩肌肉的再生至关重要。老年人废用后肌肉再生能力下降的潜在机制在很大程度上仍然是未知的，但可能与萎缩恢复相关的炎症过程的改变有关。按摩疗法在临床环境中用于帮助修复肌肉中的炎症状况，并且我们已经发现，以循环压缩负荷（CCL）的形式的按摩积极调节肌肉中的免疫反应，并有助于修复肌肉损伤和恢复年轻动物的功能。然而，按摩疗法对老年人肌肉萎缩和再生的影响是完全未知的。因此，我们推测，CCL是有益的肌肉大小的维持在废用引起的萎缩，并将改善受损的再生反应在老年大鼠。我们将以两个具体目标来研究这一假设。在目标1中，我们假设CLL通过对蛋白质周转途径的作用来减弱废用诱导的萎缩期间的肌肉质量损失。将10月龄和30月龄的雄性Fischer 344/Brown Norway大鼠后肢悬吊14天以诱导萎缩。在后肢悬吊期间，将CCL以两种不同的负荷应用于不同组大鼠的一条腿的腓肠肌。将测量肌肉大小蛋白质合成的变化、肌肉蛋白质合成和降解的标志物以及力量产生能力。在目标2中，我们假设CCL将通过其免疫调节作用改善老年大鼠肌肉的再生。将10月龄和30月龄的大鼠后肢悬吊14天，然后截肢1、2、4或14天。在再植术后立即开始，将CCL以两种不同的负荷施加于一条腿的腓肠肌，以评估CCL对萎缩后肌肉大小恢复的影响。将评估肌肉的大小，免疫细胞浸润，降解和再生，蛋白质合成和降解标记，以及力量产生能力。本申请中提出的实验将表明按摩疗法是否对一般的肌肉维持有益，特别是对老年人的肌肉大小和力量恢复有益。与年龄相关的恢复废用期间丢失的肌肉质量的能力降低具有重要的临床意义，并且开发可以预防失活诱导的萎缩或肌肉萎缩的策略至关重要。 帮助恢复废用期间失去的肌肉质量。如果我们的研究结果证明是有益的，按摩可以直接应用于临床，以维持和恢复肌肉的大小和力量。

DESCRIPTION (provided by applicant): Aging is associated with a decreased ability to recover muscle mass and strength after periods of inactivity, to which elderly are often subjected, resulting in frailty and functional dependence. Skeletal muscle is not only critically important for the development of force, but also serves as a major protein reservoir and is an important predictor of mobility, susceptibility to injury, and mortality. Therefore, it is criticaly important to design interventions to attenuate the decrease in muscle size during periods of disuse and to aid in the regrowth of atrophied muscle. Underlying mechanisms for the diminished capacity of muscle to regrow after disuse in the elderly are still largely unknown, but could be related to alterations in the inflammatory processes associated with recovery from atrophy. Massage therapy is used in clinical settings to aid in the repair of inflammatory conditions in muscles and we have found that massage in the form of cyclic compressive loading (CCL) positively modulates the immune response in muscle and aids in the repair of muscle injury and restoration of function in young animals. However, the effect of massage therapy on muscle atrophy and regrowth in the aged is completely unexplored. Therefore, we hypothesize that CCL is beneficial for the maintenance of muscle size during disuse-induced atrophy and will improve the impaired regrowth response in aged rats. We will investigate this hypothesis with two specific aims. In Aim 1 we hypothesize that CLL attenuates muscle mass lost during disuse-induced atrophy through actions on protein turnover pathways. Male Fischer 344/Brown Norway rats at 10 and 30 months of age will be hind limb suspended for 14 days to induce atrophy. CCL will be applied at two different loads in different groups of rats to gastrocnemius muscles of one leg during hind limb suspension. Changes in muscle size protein synthesis, markers of muscle protein synthesis and degradation, and force generating capacity will be measured. In Aim 2 we hypothesize that CCL will improve regrowth of muscle in aged rats through its immunomodulatory actions. Rats at 10 and 30 months of age will be hindlimb suspended for 14 days followed by ambulation for 1, 2, 4 or 14 days. CCL will be applied at two different loads to gastrocnemius muscle of one leg starting immediately after reambulation to assess the effect of CCL on recovery of muscle size after atrophy. Muscles will be assessed for size, immune cell infiltration, degradation and regeneration, and protein synthesis and degradation markers, as well as force generating capacity. The experiments proposed in this application will indicate whether massage therapy is beneficial for muscle maintenance in general and muscle size and strength restoration in the aged in particular. The age- associated diminished capacity to recover muscle mass lost during disuse is of great clinical importance and it is critically important to develop strategies that can prevent inactivity-induced atrophy or aid in the recovery of muscle mass lost during disuse. If our results prove beneficial, massage can be directly applied clinically for the maintenance and restoration of muscle size and strength.