Somitic muscle growth: a new model for the role of force in morphogenesis

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。在肌肉疾病、癌症、慢性肾衰竭、艾滋病和类风湿性关节炎中，特别是在老年人或住院患者中，肌肉萎缩是一个严重的问题。运动的物理力量通过促进肌肉生长来防止浪费。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到力量并通过生长做出反应的。在过去，我们已经发现早期肌肉是如何以类似的方式在鱼、老鼠和人身上形成的。现在，我们想研究力量在以后肌肉生长中的作用。因此，我们的首要目标是确定肌肉通常如何生长，以及力和其他信号如何影响生长。我们将使用年轻的斑马鱼，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是什么基因控制生长，c）小而易接近，这样我们就可以测量并施加在活体肌肉上的力。这些事情在哺乳动物身上更难做到。我们的第二个目标是了解肌肉如何检测力量并使用信息来协调生长。肌肉纤维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，这些附件也是力检测器，启动生长过程中的某些类型的收缩活动的反应。我们将研究纤维末端蛋白质复合物的组成和动力学，并测试其在力检测和生长反应中的作用。肌肉在生命中不断受损，通常由干细胞修复，这也有助于生长。我们的第三个目标是了解肌肉干细胞是如何形成的，它们驻留在哪里，以及力或其他信号如何调节它们的行为以协调肌肉生长和修复。骨骼、心脏和皮肤也会通过改变生长来对力作出反应。了解骨骼肌中的力检测和响应系统可能会更普遍地阐明力在生物学和再生医学中的作用。

Skeletal muscle makes up 40% of our body mass and its maintenance is essential to a good quality of life. In muscle diseases, cancer, chronic kidney failure, AIDS and rheumatoid arthritis, and particularly in older or hospitalised people, muscle wasting is a serious problem. The physical force of exercise prevents wasting by promoting 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 force and responds by growing. In the past, we have discovered how early muscle is made in similar ways in fish, mice and people. Now, we want to study the role of force in later muscle growth. So our first aim is determine how muscle normally grows and how force and other signals influence growth. We will use young zebrafish 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 what genes control growth, c) small and accessible, so we can measure and impose forces in the living muscle. These things are more difficult to do in mammals. Our second aim is to understand how muscle detects force and uses the information to orchestrate growth. Muscle fibre 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 force-detectors that initiate the process of growth in response to certain kinds of contractile activity. We will study the composition and dynamics of the protein complex at fibre ends and test its role in force detection and growth response. Muscle is continually damaged during life and is normally repaired by stem cells, which also contribute to growth. Our third aim is to understand how muscle stem cells form, where they reside, and how force or other signals regulate their behaviour to coordinate muscle growth and repair. Bone, heart and skin also respond to force by altered growth. Understanding the force detection and response systems in skeletal muscle is likely to illuminate the role of force in biology and regenerative medicine more generally.