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

肌肉力量丧失、疲劳和血糖控制受损是癌症、糖尿病、心脏病等许多疾病的常见副作用，但也会因衰老而影响健康。这些损伤存在于呼吸和腿部肌肉，导致呼吸困难和疲劳，以及做家务和园艺等日常生活活动的能力下降。肌肉无力、疲劳和血糖控制不良已被证明会导致低生活质量和早死。特别是，肌肉损伤是心衰患者死亡的一个非常有力的预测指标——心衰是一种心脏不能充分泵血的疾病。估计有1500万欧洲人患有心力衰竭，而且发病率仍在上升。最近发现，许多心力衰竭和糖尿病患者表现出更严重的症状，生存率也差得多。大多数心力衰竭和/或糖尿病患者都有严重的肌肉损伤。不幸的是，没有药物可以有效地治疗这种肌肉损伤，部分原因是我们还不了解所有的变化，也不知道是什么导致了这种情况的发生。因此，确定身体（包括细胞内部）发生了哪些变化导致了这些不利的肌肉适应，以及是什么导致了这些变化，这一点非常重要。在我们详细了解这些过程之前，我们无法轻易地开发出能够维持或改善肌肉力量和耐力的治疗方法。在过去的几年里，我们在肌肉中发现了一种叫做MuRF1的蛋白质，它似乎在心力衰竭和糖尿病中出现的肌肉无力、疲劳和葡萄糖失调中起着关键作用。我们发现心力衰竭和糖尿病会增加肌肉中MuRF1的水平。但当我们降低MuRF1水平时，比如通过运动训练，肌肉力量就会得到改善。然而，由于许多患者往往太虚弱而无法进行运动干预，我们最近开始了一项旨在通过试管实验阻断MuRF1的创新药物发现计划。我们已经确定了一种可以阻断MuRF1的新药，我们在动物身上的初步研究结果表明，它可以改善肌肉力量、耐力和血糖控制。因此，MuRF1水平升高可能是心衰和糖尿病患者运动肌肉无力、疲劳和葡萄糖失调的关键一步。然而，我们现在需要证明这个令人兴奋的想法。该项目的主要目的是提供确凿的证据，证明我们的新药可以抑制MuRF1蛋白，从而有益于心力衰竭和糖尿病患者的肌肉力量、耐力和血糖控制。为了回答这个问题，在一种方法中，我们将收集患者志愿者的肌肉活组织检查（距离腿部大约豌豆大小），我们可以将其带到我们的实验室来测量肌肉大小，力量和耐力等机械性能。我们还可以从这些人体样本中分离肌肉细胞，并添加我们的新型MuRF1药物，看看这是否能促进肌肉生长。在另一种方法中，我们将使用临床相关的心力衰竭和糖尿病小鼠模型。我们可以用与人类相同的方法让老鼠患上心力衰竭：心脏病发作。我们可以把老鼠心脏的主要冠状动脉绑起来，引起心脏病发作（心肌梗死），从而导致心脏跳动乏力——也被称为心力衰竭。我们可以通过简单地给老鼠喂食高脂肪食物来让它们患上糖尿病，这通常是人类的一个原因。然后，我们将用我们的新药物化合物治疗小鼠，以阻断MuRF1的作用。然后我们可以评估这种药物的全身治疗是否可以预防肌肉损伤，提高肌肉耐力，改善血糖控制。第二阶段将使我们能够确认这种药物是否可能成为心力衰竭和糖尿病患者的一种新的治疗选择。因此，我们的工作有可能使患者的症状、生活质量和生存受益。

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.