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Unlocking cortisol activation in muscle as a treatable cause of muscle wasting in kidney failure

解锁肌肉中的皮质醇激活作为肾衰竭肌肉萎缩的可治疗原因

基本信息

批准号：
MR/T008172/1
负责人：
Michael Sagmeister
金额：
$ 37.18万
依托单位：
University of Birmingham
依托单位国家：
英国
项目类别：
Fellowship
财政年份：
2020
资助国家：
英国
起止时间：
2020 至无数据
项目状态：
未结题

来源：
https://gtr.ukri.org/projects?ref=MR%2FT008172%2F1
关键词：
Unlocking cortisol activation muscle treatable

项目摘要

Generalised weakness is one of the most common symptoms in chronic illness. Patients often perceive weakness as their most debilitating symptom, and many find it difficult to find treatments that may help. Discovering new means to prevent and relieve weakness in chronic illness will lead to substantial benefits. Patients' quality of life could be improved drastically. Moreover, by restoring greater independence and ability to perform usual activities society, as a whole, could benefit from reduced social care expenses and increased productivity at the workplace. Chronic kidney disease (CKD) is a classic example of a pervasive condition that impairs muscle strength and the capacity of muscle to use energy. It has been known for decades that muscle wasting in kidney disease is dependent on the presence of the hormone cortisol. Although excess cortisol readily causes muscle weakness, blood levels of cortisol do not change significantly in kidney disease. This poses the unanswered question how the role of cortisol differs in health and disease. Cortisol is generated from its inactive counterpart cortisone by an enzyme called 11beta-hydroxysteroid dehydrogenase type 1 (11bHSD1) in liver, fat and muscle, in addition to its release from the adrenal glands. We and other researchers have shown that this enzyme is more active in kidney failure, leading to higher cortisol generation within tissues. Interestingly, we found this is most prominent in patients with the greatest difficulty to perform activities of daily living. Further experiments have confirmed that changes in kidney disease lead to increased generation of cortisol in muscle tissue itself, amplifying local actions of cortisol despite normal blood levels. The aim of this study is to define the role of abnormal cortisol activation within muscle tissue for muscle wasting under conditions of kidney failure and evaluate whether blocking 11bHSD1 function can prevent muscle wasting in this situation. Our research will use cell culture models whereby addition of acid or blood components from patients with kidney failure to normal human muscle cells replicates metabolic disturbances seen in kidney disease. This will allow us to examine the precise molecular mechanisms how elevated 11bHSD1 activity under kidney failure conditions interferes with insulin signalling, which normally promotes energy usage and muscle growth. We will also investigate the role of 11bHSD1 for accelerated breakdown of muscle proteins under kidney failure conditions. We anticipate that cortisol activation by 11bHSD1 takes a central role for disruptions in normal muscle metabolism that contribute to muscle weakness in CKD. After creating a detailed map showing how excess cortisol generation under kidney failure conditions impairs normal muscle function, we will aim to demonstrate the viability of blocking 11bHSD1 activity as a novel treatment in kidney failure. First, we will take muscle tissue biopsies from patients with kidney failure and attempt to correct metabolic defects in diseased muscle by blocking 11bHSD1 activity. Second, we will study mice with chronic kidney failure which have been genetically manipulated to lack 11bHSD1 function entirely or specifically in muscle tissue. Whereas mice with kidney failure usually develop muscle wasting, we anticipate that mice without 11bHSD1 function will be protected. This would prove the concept that 11bHSD1 inhibition is a promising potential treatment against muscle weakness in CKD. 11bHSD1 inhibitors for human use are already available, offering a clear route to translate our results into clinical trials and relieve the debilitating consequences of muscle weakness for patients.

全身无力是慢性病最常见的症状之一。患者通常认为虚弱是他们最虚弱的症状，许多人发现很难找到可能有帮助的治疗方法。发现新的方法来预防和减轻慢性病的虚弱将带来巨大的好处。患者的生活质量可以大大提高。此外，通过恢复更大的独立性和进行日常活动的能力，整个社会可以从减少社会护理费用和提高工作场所的生产力中受益。慢性肾脏疾病（CKD）是一种普遍性疾病的典型例子，它会损害肌肉力量和肌肉使用能量的能力。几十年来，人们已经知道肾脏疾病中的肌肉萎缩取决于激素皮质醇的存在。虽然过量的皮质醇容易导致肌肉无力，但血液皮质醇水平在肾脏疾病中不会发生显着变化。这就提出了一个尚未回答的问题，即皮质醇在健康和疾病中的作用是如何不同的。皮质醇是由其非活性对应物可的松通过肝脏，脂肪和肌肉中的一种称为11 β-羟基类固醇脱氢酶1（11bHSD 1）的酶产生的，此外还从肾上腺释放。我们和其他研究人员已经表明，这种酶在肾衰竭时更活跃，导致组织内皮质醇的产生更高。有趣的是，我们发现这在日常生活活动最困难的患者中最为突出。进一步的实验证实，肾脏疾病的变化导致肌肉组织本身皮质醇的产生增加，放大皮质醇的局部作用，尽管血液水平正常。本研究的目的是确定肾功能衰竭条件下肌肉组织内异常皮质醇激活对肌肉萎缩的作用，并评估阻断11bHSD 1功能是否可以预防这种情况下的肌肉萎缩。我们的研究将使用细胞培养模型，其中将来自肾衰竭患者的酸或血液成分添加到正常人类肌肉细胞中，复制肾脏疾病中观察到的代谢紊乱。这将使我们能够研究肾衰竭条件下11bHSD 1活性升高如何干扰胰岛素信号传导的精确分子机制，胰岛素信号传导通常促进能量使用和肌肉生长。我们还将研究11bHSD 1在肾衰竭条件下加速肌肉蛋白分解的作用。我们预计，皮质醇激活11bHSD 1在正常肌肉代谢的中断中发挥核心作用，导致CKD患者的肌肉无力。在创建了一个详细的地图，显示在肾衰竭条件下过量的皮质醇产生如何损害正常的肌肉功能后，我们的目标是证明阻断11bHSD 1活性作为肾衰竭的新治疗方法的可行性。首先，我们将从肾衰竭患者身上取肌肉组织活检，并试图通过阻断11bHSD 1活性来纠正患病肌肉中的代谢缺陷。其次，我们将研究慢性肾衰竭小鼠，这些小鼠已经被遗传操纵，完全或特异性地在肌肉组织中缺乏11bHSD 1功能。尽管肾衰竭小鼠通常会出现肌肉萎缩，但我们预计没有11bHSD 1功能的小鼠将受到保护。这将证明11bHSD 1抑制是一种有前途的潜在治疗CKD肌无力的方法。用于人类的11bHSD 1抑制剂已经可用，为将我们的结果转化为临床试验并减轻患者肌肉无力的衰弱后果提供了明确的途径。