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。肌肉质量在调节个体的新陈代谢中起着重要作用，肌肉质量的损失会导致患肥胖症和2型糖尿病的风险增加。保持肌肉质量对于确定日常生活中的身体功能尤其重要。维持肌肉质量和功能的唯一有效策略是运动疗法。通常，举重是建立背部肌肉质量的首选方法，但其他类型的快速运动（例如高强度自行车）也会有所帮助。然而，有一个主要问题，那就是每100个遵循定制监督体育锻炼计划的人中，只有40个会表现出肌肉质量的强劲增长，30个会表现出适度的改善，而30个根本不会改善。高度可变的临床反应的原因尚不清楚，但已完成的临床试验的证据表明，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份人类肌肉活检样本的基因组分析，并将其图谱与我们在实验室用药物处理细胞所产生的图谱进行了比较。这使我们能够确定可能对治疗衰老相关疾病有用的旧药物，以及一些可能干扰运动益处的药物。肌肉组织实际上由几种不同类型的细胞组成，每种细胞都在决定对运动或药物治疗的反应中发挥作用。在本研究中，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类型细胞的激活状态，并将该激活状态与监督阻力训练后注意到的增益（或缺乏）相关联。这将使我们能够了解一种或多种细胞类型是否无法正常响应锻炼计划。这种方法也使我们能够更好地了解运动激活的分子通路，因为我们以前的工作依赖于对不同细胞类型的测量结果进行平均，因为组织活检是粉碎的，将所有细胞混合在一起。这种新方法应该使我们能够创建负责肌肉质量有效增加（以及其他健康终点）的途径的更准确的签名，并更好地将这些签名与可能有助于克服低应答状态的药物签名相匹配。相同的签名还可以提供可能干扰运动康复反应的药物的读数（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，当从疾病、福尔斯或手术中康复时，老年人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-实际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.