Muscle Wasting in Uremia

描述(由申请人提供)： 6.项目摘要肌肉萎缩在晚期慢性肾脏疾病(CKD)患者中很常见，并对发病率和死亡率造成不利影响。包括对生长激素(GH)和胰岛素样生长因子-1(IGF-1)等合成代谢激素的抵抗或缺乏在内的多种因素都会导致这种消耗。此外，晚期CKD患者通常久坐不动的生活方式使他们容易肌肉萎缩，当这些受试者因病在床上不动时，这种情况会诱发或恶化。初步数据表明，CKD患者的废用性萎缩可能会被夸大，恢复可能会受到损害。这项拟议的研究的目标是更全面地了解尿毒症患者停用期间肌肉萎缩和夸大萎缩背后的机制。这项研究将从正常和终末期CKD患者、肌肉萎缩的CKD大鼠和因制动而导致的废用萎缩的CKD大鼠的肌肉活检中进行。具体目的1.探讨尿毒症对生长激素介导的人骨骼肌信号转导的影响。动物研究表明，肌肉萎缩的部分原因可能是生长激素介导的信号转导受损。这项拟议的研究将确定这是否也适用于人类。这是一项正在进行的研究。具体目的2.在大鼠身上测试慢性尿毒症会加重停用后发生的骨骼肌萎缩，并阻碍患肢活动后的恢复。另一个目的是阐明其中涉及的机制。据推测，过度的萎缩和受损的恢复主要是因为：(1)抑制了当地IGF-1的产生，增加了肌肉生长抑素的产生。PI3K/Akt/mTOR信号的激活受损，下游抑制降解和激活蛋白质合成的通路减弱，以及(3)抑制AMP激活的蛋白激酶(AMPK)活性。具体目的3.在大鼠身上测试以下任何一种手法是否可以减轻尿毒症肌肉萎缩，减少废用性萎缩，并加速康复。(1.)用重组生长激素治疗，以克服对激素的抗药性，从而刺激IGF-1的产生。(2)给予重组IGF-1以克服IGF-1缺乏和对激素的抵抗。(3)用AMPK激动剂(AICAR)激活AMPK以模拟耐力运动。这些研究将为尿毒症肌肉萎缩的机制提供新的见解，并为实现更有效地治疗尿毒症肌肉萎缩的策略这一长期目标提供基础。此外，由于肌肉萎缩的分解代谢状态在其他住院的VA患者中很常见，包括创伤后活动的患者和老年人，我们的方法具有长期潜力，不仅可以改善患有晚期CKD的退伍军人的管理，还可以改善对其他疾病的管理。 公共卫生相关性： 7.项目叙述肌肉萎缩的分解代谢状态不仅在营养不良的晚期肾功能衰竭退伍军人中很常见，而且在其他住院退伍军人中也很常见，特别是老年人、创伤后损伤的年轻人以及心力衰竭或肝硬变患者，这对发病率和死亡率都有不利影响。由于这些疾病通常需要卧床休息或有限的活动，因此停止使用肌肉萎缩会导致病情恶化，并减缓康复。尽管经常住院，但关于停用对晚期肾功能衰竭患者肌肉萎缩的影响的信息很少。我们在肾衰竭患者中提出的研究，以及肾衰竭和废用性萎缩的动物模型，应该会为肾功能衰竭的肌肉损耗和废用性萎缩的恢复机制提供新的见解。动物研究中包括了对不同治疗方案的评估，以防止肌肉萎缩并加速从废用中恢复。总体而言，所产生的知识应该为实现我们的长期目标提供基础，即制定战略，更有效地治疗肾衰竭患者的肌肉萎缩，从而改善这些患者的健康和预后。此外，由于分解代谢状态在其他住院退伍军人中很常见，特别是那些创伤后行动不便的退伍军人和老年人，我们的方法具有改善患者、退伍军人和非退伍军人的管理的长期潜力，不仅是晚期肾功能衰竭，而且还有其他疾病。

DESCRIPTION (provided by applicant): 6. Project Summary Abstract Muscle wasting is common in patients with advanced chronic kidney disease (CKD) and adversely affects morbidity and mortality. Multiple factors cause the wasting including resistance to or deficiency of anabolic hormones such as growth hormone (GH) and insulin-like growth factor 1 (IGF-1). Also, the usual sedentary life-style of advanced CKD patients predisposes them to muscle wasting and this is induced or worsened when these subjects are immobilized in bed because of illness. Preliminary data indicate that disuse atrophy may be exaggerated in CKD and that recovery may be impaired. The goal of the proposed study is to generate a more complete understanding of the mechanisms behind muscle wasting and the exaggerated atrophy that occurs during disuse in uremia. The study will be carried out with muscle biopsied from normal and end-stage CKD patients, CKD rats with muscle wasting, and CKD rats with disuse atrophy induced by immobilization. Specific Aim 1. To evaluate the effect of uremia on GH mediated signal transduction in human skeletal muscle. Animal studies indicate that muscle wasting may be due in part to impaired GH mediated signal transduction. The proposed study will determine whether this is also true for humans. This is an ongoing study. Specific Aim 2. To test the thesis in rats that chronic uremia worsens the skeletal muscle atrophy that occurs following disuse and attenuates recovery after the affected limb is mobilized. Another aim is to elucidate the mechanisms involved. It is postulated that the exaggerated atrophy and impaired recovery is mediated largely because of: (1.) depressed local IGF-1 production and increased myostatin production, (2.) impaired activation of PI3K/Akt/mTOR signaling, with attenuation of the downstream pathways that suppress degradation and activate protein synthesis, and (3.) depressed AMP-activated protein kinase (AMPK) activity. Specific Aim 3. To test in rats whether any of the following maneuvers will attenuate uremic muscle wasting, reduce disuse atrophy, and accelerate recovery. (1.) Treatment with recombinant GH to overcome resistance to the hormone and thereby stimulate IGF-1 production. (2.) Administration of recombinant IGF-1 to overcome IGF-1 deficiency and resistance to the hormone. (3.) Activation of AMPK with an AMPK agonist (AICAR) to mimic endurance exercise. These studies should provide new insight into the mechanism of muscle wasting in uremia and provide the basis for achieving the long-term goal of developing strategies for the more effective treatment of muscle wasting in uremia. Furthermore, since catabolic states with muscle wasting are common in other hospitalized VA patients, including those immobilized post-trauma and in the elderly, our approach holds the long-term potential of improving the management of veterans not only with advanced CKD, but with other illnesses. PUBLIC HEALTH RELEVANCE: 7. Project Narrative Catabolic states with muscle wasting are common not only in malnourished veterans with advanced renal failure, but also in other hospitalized VA patients, especially the elderly, in the young with post-traumatic injury, and in patients with heart failure or liver cirrhosis, and this has an adverse effect on morbidity and mortality. Since these illnesses often require bed-rest or limited mobilization, disuse atrophy of muscle sets in and worsens their condition and slows recovery. There is very little information on the impact of disuse on the muscle wasting in the patient with advanced kidney failure, even though hospitalization is frequent. The studies we have proposed in kidney failure patients and with an animal model of kidney failure and disuse atrophy should provide new insight into the mechanism of muscle wasting and recovery from disuse atrophy in kidney failure. Included in the animal studies is an evaluation of different treatment regimens to prevent muscle wasting and accelerate recovery from disuse. Overall the knowledge generated should provide the basis for achieving our long-term goal of developing strategies for the more effective treatment of muscle wasting in kidney failure patients and thereby improving the health and outcome of these patients. Furthermore since catabolic states are common in other hospitalized veterans, especially those immobilized post-trauma and the elderly, our approach holds the long- term potential of improving the management of patients, veterans and non-veterans, not only with advanced kidney failure, but also with other illnesses.