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

横纹肌的功能对我们的身体和心脏肌肉的运动至关重要，它之所以被称为横纹肌，是因为在显微镜下看到它们高度规则的条纹图案。这些条纹是由分子机器的重复排列形成的，这种机器被称为肌节，产生力量和运动。在肌节中，三种分子细丝系统共同工作：在Z盘处聚集在一起的肌动蛋白细丝，在M带聚集在一起的肌球蛋白细丝，以及连接肌动蛋白和肌球蛋白细丝的巨大蛋白质细丝titin。肌肉对使用的变化反应迅速，不使用会导致肌肉损失(称为萎缩)，运动导致肌肉生长(称为肥大)。这些过程需要不断地保持平衡，并以一种协调的方式与那些控制肌肉修复的过程联系在一起，这些过程通过制造新的蛋白质来修复肌节和替换细胞中其他不需要的或受损的成分。控制肌肉生长、萎缩和修复的信号正在出现，它们起源于M波段和Z盘。这些结构含有能够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(当肌肉被石膏固定后，肌肉在两周内迅速失去一半以上的肌肉质量就可以看出这一点)。然而，这些蛋白质中的许多仍然是谜，或者甚至还没有被发现，而且通常甚至它们最基本的功能也没有被阐明。然而，当M波段作为一种结合了结构、机械和通信功能的机械的整合因遗传缺陷或肌肉极度缺乏活动而被破坏时(例如在重症监护病房患者中)，结果是严重的肌肉疾病。这项研究将阐明M-带的组成和调节，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个巨型蛋白质--肌蛋白和暗蛋白--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.