Role of mRNA localisation and translational control in muscle growth

骨骼肌占我们身体质量的40%，它的维护对于良好的生活质量至关重要。在各种疾病中，特别是老年人或住院患者，肌肉萎缩是一个严重的问题。运动的身体活动防止浪费和增加肌肉生长。身体如何决定什么是适当的肌肉量是未知的，但一个可能的机制是肌肉收缩力的反馈。我们想知道肌肉组织是如何检测活动并通过生长做出反应的。在过去，我们已经发现早期肌肉在鱼、老鼠和人身上的发育是相似的。这种早期肌肉发育通常涉及由我们的基因控制的固定程序。现在，我们想研究活动在调节基因如何控制后期肌肉生长中的作用。为了使基因发挥作用，它们的DNA序列必须被“翻译”成氨基酸序列，从而形成构建身体的蛋白质。进行翻译的细胞机器使用基因DNA的拷贝，称为信使RNA（mRNA）作为蛋白质合成的模板。我们已经发现某些mRNA定位于肌肉纤维的末端。肌肉收缩的活动调节蛋白质从这些局部mRNA中产生的速度，从而控制肌肉的生长和功能。我们发现一种叫做BP3L的蛋白质控制着这些mRNA的翻译。因此，我们的第一个目标是确定BP3L在响应活动的正常肌肉生长中的作用。我们将使用斑马鱼胚胎和幼体，因为它们是a）透明的，这样我们就可以研究活体动物的肌肉生长，B）易于遗传操作，这样我们就可以找出哪些基因控制生长，c）小而易接近，所以我们可以很容易地控制活体肌肉的活动。这些事情在哺乳动物身上更难做到。我们的第二个目标是通过结合传统的生物化学和新的基因组学方法来发现BP3L调控的全部mRNA。这将为我们提供“大画面”，我们将利用我们在肌肉生物学方面的长期经验，专注于控制肌肉生长的特定mRNA和位于纤维末端的mRNA的功能。BP3L及其已知靶点均位于肌纤维末端。这些末端通过一组复杂的蛋白质将力传递到邻近的组织，这些蛋白质与邻近的细胞形成附着。证据使我们假设，这些附件也是活动探测器，启动生长过程中的某些类型的收缩活动的反应。因此，我们的第三个目标是了解肌肉活动如何调节BP3L，从而协调肌肉生长。与肌肉一样，神经细胞中局部mRNA的翻译受学习和记忆过程中的活动调节。因此，我们的发现可能有更广泛的应用。此外，我们将检验的一个可能的假设是，活动产生的物理力调节mRNA的翻译。阐明这种机制在整个生物学中具有重要意义，因为植物和动物中的细胞会对控制其生长的物理力量做出反应，例如皮肤结茧或受风影响的树木的生长。了解骨骼肌中的力检测和响应系统可能会阐明力在生物学和医学中的作用。

Skeletal muscle makes up 40% of our body mass and its maintenance is essential for a good quality of life. In various diseases and particularly in older or hospitalised people, muscle wasting is a serious problem. The physical activity of exercise prevents wasting and increases muscle growth. How the body decides what is an appropriate amount of muscle is unknown, but a likely mechanism is feedback from the force of muscle contraction. We want to find out how muscle tissue detects activity and responds by growing. In the past, we have discovered that early muscle develops similarly in fish, mice and people. Such early muscle development generally involves a fixed programme controlled by our genes. Now, we want to study the role of activity in regulating how genes control later muscle growth. For genes to function, their DNA sequence must be 'translated' into an amino acid sequence, thereby forming the proteins that build the body. The cellular machinery that carries out translation uses a copy of the gene DNA, known as messenger RNA (mRNA) as a template for protein synthesis. We have discovered that certain mRNAs are localised to the ends of muscle fibres. The activity of muscle contraction regulates how rapidly proteins are made from these localised mRNAs, thereby controlling muscle growth and function. We have discovered that a protein called BP3L controls translation of some of these mRNAs. So our first aim is determine the role of BP3L in normal muscle growth in response to activity. We will use zebrafish embryos and larvae because they are a) transparent, so that we can study muscle growth in the living animal, b) easy to manipulate genetically, so we can find out which genes control growth, c) small and accessible, so we can easily control activity of the living muscle. These things are more difficult to do in mammals. Our second aim is to discover the full array of mRNAs regulated by BP3L by using a combination of traditional biochemistry and new genomics methods. This will give us the 'big picture' from which we will use our long experience of muscle biology to focus on specific mRNAs controlling muscle growth and function of mRNAs located at fibre ends. Both BP3L and its known targets are located at muscle fibre ends. These ends transmit force to adjacent tissues by means of a complex set of proteins that form attachments to neighbouring cells. Evidence leads us to hypothesise that these attachments are also activity-detectors that initiate the process of growth in response to certain kinds of contractile activity. So our third aim is to understand how muscle activity regulates BP3L and thereby coordinates muscle growth. As in muscle, translation of localised mRNA in nerve cells is regulated by activity during learning and memory. So our findings may have a broader application. Moreover, one possible hypothesis that we will test is that the physical force produced by activity regulates mRNA translation. Elucidating such a mechanism would have importance throughout biology, as cells in plants and animals respond to physical forces that control their growth, for example in skin callousing or the growth of windswept trees. Understanding the force detection and response systems in skeletal muscle is likely to illuminate the role of force in biology and medicine.