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

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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.