Mitochondrial reactive oxygen species as a target for prevention of age-related loss of muscle mass and function

随着年龄的增长，我们会失去骨骼肌，这对我们承担日常任务的能力产生了重大影响，尽管这可以通过定期锻炼部分减少，但肌肉损失的机制仍然未知。一个很大的可能性是，随着年龄的增长，线粒体（我们肌肉中高度专业化的细胞器，产生我们运动所需的能量）开始释放更多的高活性分子，称为自由基或活性氧（ROS）。这些物质会损害部分肌肉细胞，并阻止它们正常工作。我们计划在局部麻醉下从不同年龄的志愿者的大腿上部肌肉中取出小块肌肉活检来研究这种可能性。以前的技术需要大量的组织来分离线粒体，但我们将使用另一种方法，将肌肉活检分成几小束肌纤维，其中线粒体保留在原位。这些可以使用技术进行研究，使我们能够评估释放的ROS量，并将其与肌肉可以施加的最大力量以及肌肉中发生的损伤量进行比较。这些研究应该使我们能够确定线粒体释放ROS增加导致与年龄相关的肌肉质量和功能丧失的可能性。该研究还将通过测试两种靶向线粒体的新型化合物的作用来研究潜在的治疗方法，以减少线粒体释放ROS。最后，如果发现这些化合物中的任何一种在其效果上有希望，我们将在老年小鼠中进行初步干预研究，以确定长期服用该药物是否可以预防老年小鼠中常见的与年龄相关的肌肉质量和功能损失。这是一个必要的第一步，以一个潜在的未来干预研究的老年人。

As we age, we lose skeletal muscle and this has a major effect on our ability to undertake everyday tasks and, although this can be partly reduced by regular exercise, the mechanisms underlying the loss of muscle remain unknown. One strong possibility is that, as we age, mitochondria (the highly specialised organelle in our muscles that generates the energy we need for movement) start to release increased amounts of highly reactive molecules called free radicals or reactive oxygen species (ROS). These species can damage parts of the muscle cell and prevent them from working properly. We plan to study this possibility on small muscle biopsies taken from the upper thigh muscles under local anaesthetic from volunteers of different ages. Previous techniques have required substantial amounts of tissue to allow isolation of the mitochondria, but we will use an alternative approach in which the muscle biopsies will be split into several small bundles of muscle fibres in which the mitochondria remain in place. These can be studied using techniques that will allow us to assess the amount of ROS released and compare this to the maximum force that the muscle can exert and to the amount of damage that has occurred in the muscle. These studies should allow us to determine the likelihood that increased release of ROS from mitochondria leads to the age-related loss of muscle mass and function. The study will also examine potential therapeutic approaches to reduce the release of ROS from mitochondria by testing the effects of 2 novel compounds that are targeted to the mitochondria. Finally if either of these compounds are found to be promising in their effects, we will undertake a preliminary intervention study in aged mice to determine whether chronic consumption of the drug can prevent the age-related loss of muscle mass and function normally seen in old mice. This is a necessary first step to a potential future intervention study in the elderly.