Disruption of redox relays in the age-related failure of muscle responses to contractile activity

我们建议研究一个被称为“氧化还原中继”的过程在骨骼肌对运动的反应中所起的作用，以及这种作用如何随着年龄的变化而变化。运动对保持骨骼肌的健康很重要，众所周知，骨骼肌对运动和其他环境变化的反应是积极的，使肌肉更强壮，更有效地工作。肌肉通过增加或减少运动后产生的不同蛋白质的含量来做到这一点。不幸的是，随着年龄的增长，这些适应性的运动变得不那么有效，越来越导致肌肉质量和功能的失败。随着肌肉运动，它产生一些非常活跃的分子，称为活性氧物质，并且已知这些物质可以作为信号来启动运动诱导的肌肉中的一些积极适应性。不幸的是，这些活性物种进行这一过程的确切方式尚不清楚，这些行为如何随着我们的年龄而变化也是未知的。其中一种活性物质是过氧化氢，它以非常低的量存在于肌肉中，是这些信号分子中最重要的。我们的研究团队在研究过氧化氢和肌肉中的其他类似物质方面有着丰富的经验，我们之前已经大体上展示了这些物质对运动后保持肌肉完整性的重要性，我们还证明了随着年龄的增长，这一过程似乎会被破坏。最近的研究表明，我们肌肉中存在的少量蛋白质可以与过氧化氢反应，并可以将过氧化氢的氧化信号传递给过氧化氢不能直接反应的其他关键蛋白质。这些中间蛋白质进行的过程被称为“氧化还原中继”，拟议的项目将研究这些“氧化还原中继”蛋白质可以从过氧化氢传递氧化信号的方式。它将确定哪些蛋白质能够做到这一点，然后与其他蛋白质反应以传递信号，然后继续刺激肌肉中的积极适应。最后，我们将确定这个过程是如何被老化所改变的。该项目的最初部分将涉及详细的分子研究，需要我们修改肌肉中的蛋白质，以了解它们的作用，这将在小鼠中进行。一旦我们确定了所涉及的途径，我们将研究这些途径的关键方面，这些方面可以在肌肉活检样本中进行测量，我们将从健康的年轻人和老年人受试者进行运动。在项目完成后，我们应该了解这些信号是如何在运动后在肌肉中传递，以刺激肌肉的积极适应，以及它们如何随着年龄的增长而变化，以及它们与老年受试者对运动的不良反应的相关性。这些信息将有助于设计合理和有针对性的干预措施，以纠正衰老的变化，并可能有利于保持老年人的肌肉力量。

We propose to study the role that a process called a 'redox relay' plays in the response of skeletal muscles to exercise and how this changes with age. Exercise is important in helping to maintain the health of our skeletal muscles and it is well known that skeletal muscle responds to exercise and to other environmental changes in a positive way to make the muscles stronger and work more efficiently. Muscle does this by increasing or decreasing the content of different proteins that are produced after exercise. Unfortunately as we age, these adaptations following exercise become less efficient, increasingly leading to a failure to maintain muscle mass and function.As muscle exercises it generates some very reactive molecules, called reactive oxygen species, and it is known that these species can act as signals to initiate some of the positive adaptations that exercise induces in muscle. Unfortunately the precise way in which these reactive species undertake this is unknown, as is how these actions change as we age. One of these reactive species is hydrogen peroxide which is present in muscles at very low amounts and is the most important of these signalling molecules. Our research team has a great deal of experience of studying hydrogen peroxide and other similar species in muscle and we have previously shown in general terms how important these species are to maintaining muscle integrity following exercise and we also demonstrated that this process appears to become disrupted as we age. Recent studies have shown that a small number of proteins present in our muscles can react with hydrogen peroxide and can transmit an oxidising signal from hydrogen peroxide to other key proteins with which hydrogen peroxide cannot react directly. The process that these intermediary proteins undertake is called a "redox relay" and the proposed project will examine the way that these "redox relay" proteins can transfer the oxidising signal from hydrogen peroxide. It will identify which proteins are able to do this, which other proteins they then react with to transfer the signal and which then go on to stimulate positive adaptations in the muscle. Finally we will determine how this process is modified by ageing. The initial part of the project will involve detailed molecular studies that require us to modify proteins in muscles in order to understand their actions and this will be undertaken in mice. Once we have identified the pathways involved we will then examine key aspects of these that can be measured in muscle biopsy samples that we will obtain from healthy young and older human subjects undertaking exercise. On completion of the project we should understand how these signals are transmitted in muscle following exercise to stimulate positive adaptations in the muscle and how they are changed by ageing and their relevance to the poor responses elderly subjects have to exercise. This information will facilitate the design of logical and targeted interventions to correct the ageing changes with potential benefits of maintaining muscle strength in the elderly.