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)人口的一半，特别容易受到肌肉质量、力量和功能丧失的影响，这些变化会导致虚弱，发病率和死亡率增加。导致老年尿毒症患者肌肉质量和功能下降的因素有很多，除了衰老和并存的情况外，缺乏运动还会加剧肌肉萎缩。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、阻力运动或联合运动，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，涉及的人数较少或缺乏对照，对长期结果的影响尚不清楚。然而，尽管有大量证据表明锻炼是有益的和具有成本效益的，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，定期锻炼被视为标准护理。摄入足够的蛋白质-卡路里也可以防止尿毒症肌肉萎缩。来自这个来源的氨基酸(AA)作为蛋白质合成的底物，也直接激活mTOR信号通路，进一步刺激蛋白质合成。在正常受试者中，如果在抗阻运动时摄入AA，合成代谢信号和蛋白质合成会增强，从而导致肌肉质量增加。运动和AA刺激的信号反应在老年MHD患者中是否完整尚不清楚，而且关于调用的细胞过程的信息也很少。综上所述，我们计划测试这一假设，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，我们将研究蛋白质补充剂是否能显著增强运动刺激的合成代谢信号。65-80岁的功能受损的MHD患者将被随机分为两组，每组30人，一组接受运动训练，另一组接受常规护理。3个月后，每组一半的人将接受一次性的蛋白质卡路里补充，而另一半将在一场急性运动中接受安慰剂，并将对肌肉进行活组织检查，以检查信号反应。基线和3个月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、脂肪和生化状况，以及活检肌肉的形态和分子分析。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记物。对运动和营养补充诱导老年MHD患者肌肉合成代谢反应的机制将提供新的见解，这可能作为制定对抗这些人肌肉质量和功能丧失的策略的基础。最后，我们预计我们的锻炼计划将是“用户友好的”，因此可能成为老年MHD患者日常护理的一部分，或许还有年轻的MHD患者。如果这项研究对老年人有明显的短期益处，它可能会成为更广泛的长期结果研究的基础。

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.