Muscle Wasting in Uremia

描述（由申请人提供）： 6.摘要肌肉萎缩在晚期慢性肾脏病（CKD）患者中很常见，并对发病率和死亡率产生不利影响。多种因素导致消瘦，包括对合成代谢激素如生长激素（GH）和胰岛素样生长因子1（IGF-1）的抵抗或缺乏。此外，晚期CKD患者通常的久坐不动的生活方式使他们易于肌肉萎缩，并且当这些受试者因疾病而卧床不动时，这会诱发或恶化。初步数据表明废用性萎缩可能在CKD中被夸大，并且恢复可能受损。这项研究的目的是更全面地了解尿毒症废用性肌肉萎缩和过度萎缩的机制。本研究将采用正常和终末期CKD患者、肌肉萎缩的CKD大鼠和制动诱导废用性萎缩的CKD大鼠的肌肉活检进行。 具体目标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，肌肉萎缩可能部分是由于GH介导的信号转导受损。这项拟议中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。 具体目标2。在大鼠中验证慢性尿毒症会使废用后发生的骨骼肌萎缩，并减弱患肢活动后的恢复。另一个目的是阐明所涉及的机制。据推测，夸大的萎缩和受损的恢复是介导的，主要是因为：（1）。抑制局部IGF-1的产生并增加肌肉生长抑制素的产生，（2.）PI 3 K/Akt/mTOR信号传导的活化受损，抑制降解和活化蛋白质合成的下游途径减弱，和（3.）抑制AMP活化蛋白激酶（AMPK）活性。 具体目标3。在大鼠中测试以下任何操作是否会减轻尿毒症性肌肉萎缩，减少废用性萎缩，并加速恢复。（1.）用重组GH治疗以克服对激素的抗性，从而刺激IGF-1的产生。（2.）施用重组IGF-1以克服IGF-1缺乏和对激素的抗性。（3.）用AMPK激动剂（AICAR）激活AMPK以模拟耐力运动。 这些研究应该为尿毒症肌肉萎缩的机制提供新的见解，并为实现制定更有效治疗尿毒症肌肉萎缩的策略的长期目标提供基础。此外，由于分解代谢状态伴肌肉萎缩在其他住院的VA患者中很常见，包括那些创伤后固定的患者和老年人，我们的方法不仅具有改善晚期CKD退伍军人管理的长期潜力，而且具有其他疾病。 公共卫生相关性： 7.伴有肌肉萎缩的分解代谢状态不仅在营养不良的晚期肾衰竭退伍军人中很常见，而且在其他住院的VA患者中也很常见，尤其是老年人、创伤后损伤的年轻人以及心力衰竭或肝硬化患者，这对发病率和死亡率有不利影响。由于这些疾病通常需要卧床休息或有限的活动，肌肉的废用性萎缩会影响他们的病情并减缓恢复。关于废用对晚期肾衰竭患者肌肉萎缩影响的信息很少，尽管住院治疗很频繁。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为肾衰竭中肌肉消耗和废用性萎缩的恢复机制提供新的见解。动物研究包括对不同治疗方案的评估，以防止肌肉萎缩和加速废用恢复。 总的来说，所产生的知识应该为实现我们的长期目标提供基础，即制定更有效治疗肾衰竭患者肌肉萎缩的策略，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，特别是那些创伤后固定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管理的长期潜力，不仅有晚期肾衰竭，而且有其他疾病。

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.