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

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.

Patients with renal failure suffer reduced functional status, low quality of life and higher morbidity due to muscle wasting. Uraemia and acidosis disturb metabolism in skeletal muscle, leading to insulin resistance and protein loss. This process requires glucocorticoids (GC) as a critical co-factor. My new data show that GC signals are amplified within skeletal muscle by the 11bHSD1 enzyme in uraemic conditions.

I aim to clarify how intramuscular GC activation by 11bHSD1 contributes to insulin resistance and muscle atrophy in renal failure, and test 11bHSD1 inhibition as a novel therapy in pre-clinical models.

I will use primary healthy human muscle cell cultures stimulated with uraemic serum or acidosis to model renal failure in vitro. In this system, I will determine the role of 11bHSD1 activity for insulin resistance and protein degradation using biomolecular and functional metabolic assays.
I will correlate findings from the in vitro model with experiments on muscle biopsies from patients with kidney failure. Using uraemic human muscle ex vivo and derived primary cultures, I will test the capacity to reverse metabolic defects through 11bHSD1 inhibition.
To test therapeutic viability of 11bHSD1 inhibition in vivo, I will study mice with uraemia and 11bHSD1 deletion systemically or in muscle. Metabolic and muscular phenotype will be assessed by in vivo muscle strength, muscle weight, histology, GC metabolism analysis and biomolecular assays.

Opportunities are:
- Unravel mechanisms whereby GC contribute to muscle dysfunction, leading to transferrable insights for other diseases and new prevention strategies
- Pioneer primary muscle culture to study uraemic muscle complications
- Unlock 11bHSD1 inhibition as a potential treatment for muscle wasting in CKD and other chronic illnesses, helping patients to remain independent and healthier
- Refine commercial value and medical application of 11bHSD1 inhibiting pharmaceuticals in development

Chronic kidney disease (CKD) is estimated to affect 6.5 million people in Britain. Even mild to moderate CKD disturbs normal muscle function. Generalised weakness and fatigue are common but intractable complications. People with CKD and muscle wasting often cannot perform normal activities and have lower quality of life. They also suffer from more depression, cardiovascular disease, hospitalisations and early death. The burden on health and social care from muscle wasting in CKD is expanding due to aging populations and rising frailty. Yet, effective and acceptable management options are lacking.

Significant gaps in knowledge exist on the origin of muscle wasting in CKD. This is reflected by hardly any new treatments under evaluation (2 active drug trials world-wide, February 2019, clinicaltrials.gov). This project will generate impact by clarifying the origin of muscle wasting and exploring new preventions and treatments.

Benefit to Researchers
Our research will advance scientists' grasp of the processes leading to abnormal muscle metabolism in CKD. It will integrate known risk factors of inflammation, acidosis, insulin resistance and steroid hormones into a clearer, more cohesive picture. We also aim to explain causes for impaired insulin signalling, which links with cardiovascular disease besides muscle wasting. Beyond CKD, these fundamental insights will be transferrable to similar problems in critical illness or lung diseases. Hence, we expect our results to inspire new questions and propel scientific advances across a broad range of medical research.

We use innovative animal research and cell culture techniques. Experiments aim to closely resemble human biology to make them applicable to health and disease. Promoting sophisticated research approaches will help other researchers to use such tools. This will ultimately improve the quality of related medical research.

Benefit to Patients and Clinicians
Our research will educate us on risks and prevention strategies for muscle wasting in CKD. Unravelling links between CKD, muscle wasting, cortisol activation, acidosis and diabetes will ultimately help clinicians to manage vulnerable patient groups. Moreover, steroid medications are commonly prescribed in CKD. Our results will shed light on their adverse effects and how to mitigate them.

Discovery of novel therapies for patients with CKD is a key aim. We will test the principle of blocking 11bHSD1 to prevent muscle wasting in preclinical studies. This would lay the foundations for clinical trials and create access to new treatments, ultimately improving lives for patients and their families. Available 11bHSD1 blockers for human use appear safe and effective. Repurposing these drugs will make it feasible and economical to translate our preclinical results to clinical testing.

Benefit to Pharmaceutical Industry
Companies with investments in 11bHSD1 blockers stand to profit from our data. These drugs are currently under evaluation for metabolic syndrome, dementia and other conditions. Our research will inform 'off target' effects on muscle health, thereby directing therapeutic refinement. In addition, identifying muscle wasting as a new indication would increase revenue from these drugs. Economic advantages from our research can come from resource allocation for drug development, better clinical trial design and new university-industry partnerships.

Benefit to Medicines Regulating Authorities
Our research will provide original data that can assist regulatory agencies in licensing and safety decisions relating to 11bHSD1 blockers.

Benefit to Health & Social Care and Society
Potentially the greatest gains are to be achieved through ultimately protecting patients' functional status and ability to perform usual activities. Not only will this substantially reduce care pressures on health and social services, it would also allow more people with chronic illness to remain productive members of society.