Sarcomere proteostasis in titinopathies

横纹肌的功能，之所以这么叫是因为在显微镜下观察时它们的高度规则的条纹图案，对我们的身体和心脏肌肉的运动至关重要。这些条纹是由分子机器的重复排列形成的，这些分子机器被称为肌节，可以产生力量和运动。在肌节中，三种分子丝系统一起工作：肌动蛋白丝，它们在Z盘处结合在一起;肌球蛋白丝，它们在M带处结合在一起;以及巨大的蛋白丝肌联蛋白，它连接肌动蛋白丝和肌球蛋白丝。肌肉对使用的变化反应迅速，废用导致肌肉损失（称为萎缩），运动导致肌肉生长（称为肥大）。这些过程需要不断平衡，并以协调的方式与那些控制肌肉修复的过程联系起来，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或受损的成分。控制肌肉蛋白质周转的信号正在出现，起源于M带和Z盘。这些结构包含可以感知机械应力并控制蛋白质降解机制活性的蛋白质。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带作为结合结构、机械和通信功能的机器的整合被遗传缺陷破坏时，就会导致严重的肌肉疾病。这项研究将阐明M带的组成和调节，其作为蛋白质稳态调节剂的作用，以及为什么参与其组装的两种巨大蛋白质Titin和Obscurin的突变会导致肌肉疾病。巨肌蛋白肌联蛋白是人体中最大的蛋白质，它的遗传缺陷越来越多地被认为是各种肌肉疾病的常见原因。这些突变中的许多导致有缺陷的蛋白质，肌肉细胞需要通过聚集在一起并干扰正常功能来防止异常行为，这可能是一种主要的疾病机制。我们将研究肌联蛋白中的密码改变“错义”突变对细胞科普缺陷蛋白的能力的影响，称为蛋白质质量控制。这些发现将有助于我们了解肌节如何调节肌节质量控制的基本机制，以及这种基本机制在主要影响儿童的严重遗传性肌病中是如何受到干扰的。

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 protein turnover are emerging to originate at the M-band and the Z-disk. These structures contain proteins that can sense mechanical stress and control the activity of the protein degradation machinery. 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, severe muscle diseases are the result. This study will shed light on the compositions and regulation of the M-band, its role as a regulator of proteostasis, and why mutations in two of the giant proteins that are involved in its assembly, titin and obscurin, can lead to muscle disease. Inherited defects in the giant muscle protein titin, the largest in the human body, are increasingly identified as common causes of a broad range of muscle diseases. Many of these mutations cause defective proteins that the muscle cell would need to prevent from behaving abnormally by clumping together and interfering with normal function, which may be a major disease mechanism. We will study the impact of code-changing "missense" mutations in titin on the ability of the cell to cope with defective proteins, called protein quality control. The findings will help us to understand the basic mechanisms of how sarcomeres regulate sarcomere quality control, and how this fundamental mechanism is perturbed in severe inherited myopathies affecting mainly children.