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

全身无力是慢性病中最常见的症状之一。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用的治疗方法。发现预防和缓解慢性疾病虚弱的新方法将带来实质性的好处。患者的生活质量可以得到极大的改善。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）是一种普遍存在的损害肌肉力量和肌肉使用能量能力的疾病的典型例子。几十年来，人们已经知道肾脏疾病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引起肌肉无力，但肾脏疾病患者血液中的皮质醇水平没有显著变化。这就提出了一个悬而未决的问题，皮质醇在健康和疾病中的作用是如何不同的。除了从肾上腺释放外，肝脏、脂肪和肌肉中的一种名为11β -羟基类固醇脱氢酶1型（11bHSD1）的酶也会产生皮质醇。我们和其他研究人员已经证明，这种酶在肾衰竭中更活跃，导致组织内皮质醇分泌增多。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中皮质醇的产生增加，尽管血液水平正常，但皮质醇的局部作用却被放大。本研究的目的是确定肌肉组织内异常皮质醇激活在肾衰竭条件下肌肉萎缩中的作用，并评估阻断11bHSD1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，将来自肾衰竭患者的酸或血液成分添加到正常的人体肌肉细胞中，复制肾脏疾病中所见的代谢紊乱。这将使我们能够研究肾衰竭条件下11bHSD1活性升高如何干扰胰岛素信号的精确分子机制，而胰岛素信号通常促进能量使用和肌肉生长。我们还将研究11bHSD1在肾衰竭条件下加速肌肉蛋白分解的作用。我们预计11bHSD1的皮质醇激活在导致CKD肌肉无力的正常肌肉代谢中断中起核心作用。在创建了肾衰竭条件下过量皮质醇生成如何损害正常肌肉功能的详细地图后，我们将旨在证明阻断11bHSD1活性作为肾衰竭新治疗方法的可行性。首先，我们将对肾衰竭患者进行肌肉组织活检，并尝试通过阻断11bHSD1活性来纠正病变肌肉的代谢缺陷。其次，我们将对患有慢性肾衰竭的小鼠进行研究，这些小鼠通过基因操纵使其在肌肉组织中完全或特异性地缺乏11bHSD1功能。而患有肾衰竭的小鼠通常会出现肌肉萎缩，我们预计没有11bHSD1功能的小鼠将受到保护。这将证明11bHSD1抑制是一种治疗CKD肌肉无力的有希望的潜在治疗方法。人类使用的bhsd1抑制剂已经可用，为将我们的结果转化为临床试验提供了一条明确的途径，并减轻了患者肌肉无力的衰弱后果。

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.