Developing Spatially Resolved Molecular Drug-Repurposing Assays for Treating Age-Related Frailty

随着年龄的增长，人们会失去骨骼肌组织。肌肉量在调节个人新陈代谢方面起着重要作用，肌肉量的减少会增加患肥胖症和二型糖尿病的风险。维持肌肉质量对于决定日常生活中的身体机能尤其重要。保持肌肉质量和功能的唯一有效策略是运动疗法。一般来说，举重是锻炼背部肌肉的首选方法，但其他类型的快速运动（如高强度骑自行车）也会有所帮助。然而，有一个主要的问题，那就是每100个人在遵循一个量身定制的有监督的体育锻炼计划后，只有40个人的肌肉质量会有明显的增加，30个人的肌肉质量会有适度的改善，而30个人的肌肉质量根本没有改善。临床反应差异很大的原因尚不清楚，但已完成的临床试验证据表明，这不太可能是由正常饮食中缺乏蛋白质引起的，也与训练方案的类型无关。事实上，它很可能是由遗传因素和与其他环境因素的相互作用引起的，包括临床前疾病和潜在的处方药。我们已经完成了数千个人体肌肉活检样本的基因组图谱，并将它们的图谱与我们在实验室用药物治疗细胞所产生的图谱进行了比较。这使我们能够识别出可能对治疗与衰老有关的疾病有用的旧药物，也可以识别出一些可能会干扰运动益处的药物。肌肉组织实际上是由几种不同类型的细胞组成的，每一种细胞都在决定对运动或药物治疗的反应中发挥作用。在目前的研究中，我们希望使用一种称为“空间转录组学”的新技术来研究每种类型细胞的基因组反应。这使我们能够了解运动后每种细胞的激活状态，并将激活状态与监督阻力训练后注意到的增益（或缺失）联系起来。这将使我们能够了解一种或多种细胞类型是否无法对锻炼计划做出正常反应。这种方法还使我们能够更好地理解运动激活的分子途径，因为我们之前的工作依赖于对不同细胞类型的测量进行平均，因为组织活检是粉碎的，将所有细胞混合在一起。这种新方法应该允许我们创建更准确的信号通路，负责有效增加肌肉质量（以及其他健康终点），并更好地将这些信号与可能有助于克服低反应状态的药物信号相匹配。同样的特征也可以提供可能干扰运动康复反应的药物的数据（例如，在临床试验中发现扑热息痛和二甲双胍都限制了训练反应），因此，当老年人从疾病、跌倒或手术中康复时，可以在完成物理治疗的同时暂时停用这些药物。新知识的应用——包括实际应用和潜在的生物技术应用——有可能使英国和全球的老龄人口过上更健康、更充实的生活。

As people age, they lose skeletal muscle tissue. Muscle mass plays an important role in regulating an individual's metabolism and loss can lead to an increased risk of developing obesity and type two diabetes. Maintaining muscle mass is especially critical for determining physical function in everyday life. The only effective strategy for maintaining muscle mass and function is exercise therapy. Typically, weight-lifting is the preferred method for building back muscle mass however other types of brisk exercise (e.g. high-intensity cycling) will help. There is one major issue, however, and that is that for every 100 people that follow a tailored supervised physical exercise program only 40 will demonstrate robust gains in muscle mass, 30 will demonstrate modest improvements while 30 will not improve at all. The reason for the highly variable clinical response is unknown, however the evidence from completed clinical trials indicates that it is unlikely to be caused by lack of protein in a normal diet nor is it related to the type of training protocol. In fact, it is most likely caused by genetic factors and interactions with additional environmental factors, including preclinical disease and potentially prescribed drugs. We have completed the genomic profiling of thousands of human muscle biopsy samples and compared their profiles to those we can create by treating cells in the lab with drugs. This has allowed us to identify old drugs that might be useful for treating aging related diseases and also some that may interfere with the benefits of exercise. Muscle tissue is actually composed of several different types of cells and each plays a role in determining the responses to exercise or drug treatment. In the present study, we wish to study the genomic responses in each type of cell using a new technology called 'spatial transcriptomics'. This allows us to understand the activation status of each type of cell, following exercise, and relate that activation status to the gains (or lack of) noted after supervised resistance training. This will enable us to understand if one or more cell type is failing to respond normally to the exercise program. This method also allows us to better understand the molecular pathways activated by exercise, as our previous work relies on averaging the measurements across different cell types because the tissue biopsy is pulverised, mixing all the cells together. This new method should allow us to create more accurate signatures of the pathways responsible for effective gains in muscle mass (as well as other health endpoint points) and better match those signatures to drug-signatures that might help over-come low responder status. The same signatures can also provide a readout of drugs that might interfere with exercise rehabilitation responses (e.g., both paracetamol and metformin have been found to limit training responses in clinical trials) and older individuals can therefore, when being rehabilitated from illness, falls or surgery, be temporarily taken off those medications while completing their physical therapy. The application of the new knowledge - both practical and potential biotechnological application - has the potential to enable aging populations, in the UK and globally, to live a healthier fulfilling life.