Exercise to Prevent Muscle Mass and Functional Loss in Elderly Dialysis Patients

描述（由申请人提供）： 老年患者占终末期肾病（ESRD）人群的一半，特别容易遭受肌肉质量、力量和功能损失-这些变化导致虚弱和发病率和死亡率增加。许多因素导致老年尿毒症患者肌肉质量和功能下降，除了衰老和合并症外，缺乏活动会使消瘦恶化。对维持性血液透析（MHD）患者的研究表明，定期运动，包括有氧运动、阻力运动或综合运动，可以抵消这些患者肌肉质量和功能的损失。然而，大多数研究没有专门针对老年人，涉及的人数很少或缺乏对照，对长期结果的影响尚不清楚。然而，尽管有大量证据表明运动有益且具有成本效益，但它并不是MHD患者常规护理的一部分。相比之下，在患有心血管疾病和其他与肌肉萎缩相关的疾病的患者中，定期运动被视为标准护理。适当的蛋白质-热量摄入也可以提供一些预防尿毒症肌肉萎缩的保护。来自该来源的氨基酸（AA）用作蛋白质合成的底物，并且还直接激活进一步刺激蛋白质合成的mTOR信号传导途径。在正常受试者中，如果在抗阻运动时摄入AA，则合成代谢信号和蛋白质合成增强，这导致肌肉质量增加。老年MHD患者的运动和AA刺激的信号反应是否完整尚不清楚，并且关于所调用的细胞过程的信息很少。综上所述，我们计划验证一个假设，即对心脏病患者有效的家庭锻炼计划将改善老年MHD患者的心肺功能和肌肉质量和功能。此外，在一项初步研究中，我们将检查蛋白质补充剂是否能急性增强运动刺激的合成代谢信号。将65-80岁的功能受损MHD受试者随机分为两组，每组30例，一组接受运动训练，另一组接受常规护理。3个月后，每组中的一半将接受一次性蛋白质-卡路里补充剂，而另一半将在急性运动期间接受安慰剂，并对肌肉进行活检以检查信号反应。基线和3个月时的评估将包括心肺功能、肌肉力量和功能、大腿肌肉体积和组成、全身组成、生活质量（QOL）、认知功能、营养、炎症、脂质和生化状态以及活检肌肉的形态学和分子分析。我们预计，家庭锻炼将抵消肌肉萎缩，提高心肺和肌肉功能和生活质量，并减少长期结果的替代标志物。运动和营养补充剂诱导老年MHD患者肌肉合成代谢反应的机制将提供新的见解，这可能作为设计策略的基础，以抵消这些人的肌肉质量和功能的损失。最后，我们预计我们的运动计划将是“用户友好的”，因此可能成为老年人，也许是年轻的MHD患者的日常护理的一部分。如果这项研究在老年人中的短期益处是明显的，它可以为更广泛的长期结果研究奠定基础。

DESCRIPTION (provided by applicant): Elderly patients comprise half of the end-stage renal disease (ESRD) population and are particularly vulnerable to loss of muscle mass, strength and function - changes that lead to frailty and increased morbidity and mortality. Many factors contribute to the decline in muscle mass and function in the elderly uremic, and apart from aging and co-morbid conditions, wasting is worsened by inactivity. Studies in maintenance hemodialysis (MHD) patients have shown that regular exercise, including aerobic, resistance or combined modalities, can counteract the loss of muscle mass and function in these patients. However, most studies have not specifically targeted the elderly, have involved small numbers or lacked controls, and the impact on long-term outcomes is unknown. Nevertheless, despite substantial evidence indicating that exercise is beneficial and cost-effective, it is not part of the routine care of MHD patients. In contrast, among patients with cardiovascular disease and other conditions associated with muscle wasting, regular exercise is regarded as standard of care. Some protection against uremic muscle wasting can also be afforded by an adequate protein-calorie intake. Amino acids (AA) from this source serve as substrates for protein synthesis and also directly activate the mTOR signaling pathway which further stimulates protein synthesis. In normal subjects, if AA are ingested at the time of resistance exercise, anabolic signaling and protein synthesis are enhanced and this leads to increased muscle mass. Whether the exercise and AA-stimulated signaling response is intact in elderly MHD patients is unknown, and there is little information regarding the cellular processes invoked. Taking this all together, we plan to test the hypothesis that a home-based exercise program, effective in cardiac patients, will improve cardiopulmonary function and muscle mass and function in elderly MHD patients. In addition, in a pilot study we will examine whether a protein supplement acutely enhances exercise- stimulated anabolic signaling. Functionally impaired MHD subjects aged 65-80 years will be randomized into two groups of 30 each, one undergoing exercise training and the other usual care. After 3 months, half of each group will receive a one-time protein-calorie supplement while the other half will receive placebo during an acute bout of exercise, and muscle will be biopsied for examining the signaling response. Assesments at baseline and 3 months will include cardiopulmonary function, muscle strength and function, thigh muscle volume and composition, whole body composition, quality of life (QOL), cognitive function, nutritional, inflammatory, lipid and biochemical status, and morphologic and molecular analyses of biopsied muscle. We anticipate that home-based exercise will counteract muscle wasting, enhance cardiopulmonary and muscle function and QOL, and reduce surrogate markers of long-term outcome. New insights into mechanisms whereby exercise and nutrient supplementation induce an anabolic response in muscle of elderly MHD patients will be provided, which may serve as a basis for devising strategies to counteract loss of muscle mass and function in these individuals. Finally, we anticipate that our exercise program will be "user-friendly" and may thus form part of routine care of elderly, and perhaps younger MHD patients. If short-term benefits are evident from this study in the elderly, it could form the basis for a broader long-term outcomes study.