Muscle RING Finger 1 as a signalling hub for muscle atrophy, mitochondrial dysfunction, and insulin resistance in heart failure and diabetes

点击翻译按钮获取中文摘要

Loss of muscle strength, tiredness, and impaired glucose control are common side-effects in many illnesses such as cancer, diabetes, heart disease, but also in health due to ageing. These impairments are found in both the breathing and leg muscles, which lead to breathlessness and fatigue and a reduced ability to do activities of daily living such as housework and gardening. Muscle weakness, fatigue, and poor glucose control have been shown to contribute to a low quality of life and an earlier death. In particular, muscle damage is a very strong predictor of death in patients with heart failure - a disease in which the heart fails to adequately pump blood. An estimated 15 million Europeans have heart failure and rates are still increasing. Recently it has been found that many patients with heart failure and diabetes show greater symptoms and have a much worse survival. Most patients with heart failure and/or diabetes suffer from severe muscle damage. Unfortunately, no drugs are available to effectively treat this muscle damage, partly because we do not yet understand all of the changes or what makes this happens. Therefore, it is very important we identify what changes are occurring in the body (including inside the cells) that cause these adverse muscle adaptations, and also what sets these changes in motion. Until we understand in detail these processes, we cannot easily develop treatments that allow muscle strength and endurance to be maintained or improved. Over the last years, we have found a protein in the muscle termed MuRF1, which seems to play a key role in muscle weakness, tiredness, and glucose dysregulation seen in heart failure and diabetes. We have found that heart failure and diabetes have increased levels of MuRF1 in the muscle. But when we reduce MuRF1 levels, for example by exercise training, muscle strength is improved. However, as many patients are often too weak to perform exercise interventions, we recently started an innovative drug discovery programme aimed at blocking MuRF1 using test tube experiments. We have identified one novel drug that could block MuRF1 and our preliminary findings in animals have shown can improve muscle strength, endurance, and glucose control. As such, elevated MuRF1 levels may represent a critical step that sets in motion muscle weakness, tiredness, and glucose dysregulation in patients with heart failure and diabetes. However, we now need to prove this exciting idea.The main aim of this project is to provide conclusive evidence that our novel drug can inhibit the MuRF1 protein to benefit muscle strength, endurance, and glucose control in heart failure and diabetes. To answer this, in one approach we will collect muscle biopsies from patient volunteers (around a pea size amount from the leg), which we can take to our laboratory to measure mechanical properties such as muscle size, strength and endurance. We can also isolate muscle cells from these human samples and add our novel MuRF1 drug to see if this improves muscle growth. In another approach, we will use clinically-relevant mouse models of heart failure and diabetes. We can give mice heart failure in the same way as it happens in humans: by a heart attack. We can tie off the main coronary artery in the heart of mice to cause this heart attack (myocardial infarction), which leads to heart pumping weakness - also known as heart failure. We can give mice diabetes by simply feeding them a high fat diet, which is often a cause in humans. We will then treat mice with our new drug compound to block the effects of MuRF1. We can then assess if whole-body treatment of this drug can prevent muscle damage, improve muscle endurance, and improve glucose control. This second phase will allow us to confirm whether the drug might represent a new treatment option for patients with heart failure and diabetes. Our work therefore has the potential to benefit symptoms, quality of life and survival in patients.