Sarcomeric signalling by giant muscle M-band proteins in health and disease

横纹肌的功能对我们身体和心脏肌肉的运动至关重要。横纹肌之所以被称为横纹肌，是因为在显微镜下观察时，它们的条纹模式非常规则。这些条纹是由分子机器的重复排列形成的，称为肌节，产生力量和运动。在肌节中，三个分子丝系统一起工作：肌动蛋白丝，在z盘连接在一起；肌凝蛋白丝，在m带连接在一起；以及连接肌动蛋白和肌凝蛋白丝的巨大蛋白丝联蛋白。肌肉对使用的变化反应迅速，不使用导致肌肉损失（称为萎缩），锻炼导致肌肉生长（称为肥大）。这些过程需要不断平衡，并以协调的方式与控制肌肉修复的方式联系在一起，通过制造用于肌节修复的新蛋白质和替换细胞中其他不需要或受损的成分。控制肌肉生长、萎缩和修复的信号开始发源于m带和z盘。这些结构含有可以感知机械应力的蛋白质，机械应力是控制肌肉生长和萎缩的最重要因素（当肌肉用石膏固定时，两周内肌肉量迅速减少一半以上）。然而，这些蛋白质中的许多仍然是谜，甚至还没有被发现，甚至它们最基本的功能也没有被阐明。然而，当m波段作为一种集结构、机械和通讯功能于一体的机械的整合被遗传缺陷或肌肉极度不活动（例如在重症监护病房的病人中）所破坏时，就会导致严重的肌肉疾病。这项研究将阐明m波段的组成和调控，它作为机械应力传感器的作用，以及为什么参与其组装的两种巨蛋白（titin和obscurin）的突变会导致肌肉疾病。

The function of striated muscles, so called because of their highly regular striation pattern when viewed in a microscope, is crucial for the movement of our body and heart muscles. These stripes are formed from the repetitive arrangements of molecular machines, called sarcomeres that generate force and movement. In the sarcomere, three systems of molecular filaments are working together: actin filaments, which are held together at the Z-disk, myosin filaments, held together at the M-band, and the giant protein filament titin, which links the actin and myosin filaments. Muscle responds rapidly to changes in use, with disuse leading to muscle loss (called atrophy) and exercise leading to muscle growth (called hypertrophy). These processes need to be constantly balanced, and are linked in a coordinated way to those controlling muscle repair by making new proteins for sarcomere repair and replacement of other unwanted or damaged components of the cell. Signals controlling muscle growth, atrophy and repair signals are emerging to originate at the M-band and the Z-disk. These structures contain proteins that can sense mechanical stress, the most important factor controlling muscle growth and atrophy (as seen by the rapid loss of more than half the muscle mass in two weeks when muscles are immobilised in a plaster cast). Many of these proteins, however, remain enigmatic or haven't even been discovered, and often even their most fundamental functions have not been elucidated. Yet, when the integration of the M-band as a machinery combining structural, mechanical and communication functions is disrupted by genetic defects or extreme muscle inactivity (for instance in intensive care unit patients), severe muscle diseases are the result. This study will shed light on the compositions and regulation of the M-band, its role as a sensor for mechanical stress, and why mutations in two of the giant proteins that are involved in its assembly, titin and obscurin, can lead to muscle disease.