MICA: Determining how mutations in myosin cause skeletal muscle disease

骨骼肌约占人体的40%。不足为奇的是，有各种各样的疾病会影响肌肉结构和功能。其中之一是一种肌肉萎缩疾病，它是由一种名为肌球蛋白的蛋白质突变引起的。骨骼肌是一种高度规则的结构，由从一端到另一端的肌肉纤维组成，在那里它们结束于肌腱。肌肉纤维是由数千个细胞融合在一起，形成一个包含数千个细胞核的单个巨细胞。在肌肉纤维中，两种主要的蛋白质相互作用，使肌肉纤维变短，它们被组织成一个高度规则的重复单位模式，称为肌肉肌节。这些纤维被首尾相连地组织成称为肌原纤维的长长结构，从纤维的一端延伸到另一端。一根纤维中充满了肌原纤维，约占纤维总体积的80%。单个纤维可以有大约200毫米长，而单个肌节只有大约2微米长，这意味着从肌原纤维的一端到另一端大约有10万个肌节。在每个肌节内，肌球蛋白被组织成粗丝，它们之间的肌动蛋白被组织成细丝。当肌肉收缩时，粗纤维中肌球蛋白的投射(交叉桥)与细纤维中的肌动蛋白相互作用。这些拉力拉动细丝，导致每个肌节缩短约10%。每个肌节内的每一个小动作都沿着肌肉纤维汇总，在其末端产生更大的运动，从而使肌肉能够移动关节。为了让这一切发挥作用，肌球蛋白必须被精确地组织成粗大的细丝。事实上，每根粗纤维正好含有294个肌球蛋白分子。在一些类型的肌肉衰减性疾病中，如莱恩早发性远端肌病，肌球蛋白中对形成粗丝至关重要的部分发生了突变。我们认为这意味着粗丝没有正确形成，导致观察到的肌肉萎缩。我们的研究将阐明这一观点，帮助我们了解肌球蛋白突变是如何导致肌肉萎缩的。我们将研究突变对肌球蛋白这一部分结构的影响，并确定突变如何影响肌球蛋白整合成粗丝的能力。

Skeletal muscle makes up about 40% of the human body. Not surprisingly there are a wide range of diseases that affect muscle structure and function. One of these is a type of muscle wasting disease, which is caused by mutations in a protein called myosin. Skeletal muscle is a highly regular structure, consisting of muscle fibres that run from end to end, where they end in the muscle tendons. Muscle fibres are formed by the fusion of many thousands of cells together to form a a single giant cell that contains thousands of nuclei. Within the muscle fibre the two main proteins that interact to make the muscle fibre shorten are organised into a highly regular pattern of repeating units called muscle sarcomeres. These are organised end to end into long structures called myofibrils, which run from one end of the fibre to the other. A single fibre is packed full of myofibrils, which make up about 80% of the total volume of the fibre. A single fibre can be about 200 mm long, whereas a single sarcomere is only about 2 microns long, which means there are around 100,000 sarcomeres from one end of the myofibril to the other. Inside each sarcomere, myosin is organised into thick filaments and between them actin is organised into thin filaments. When muscle contracts, projections (crossbridges) from myosin in the thick filaments interact with actin in the thin filaments. These pull on the thin filaments causing each sarcomere to shorten by about 10%. Each of these small movements within each sarcomere are summed along the muscle fibre to generate much larger movements at their ends, enabling movement of joints by the muscle. For all of this to work, myosin must be precisely organised into the thick filaments. Indeed each thick filament contains exactly 294 molecules of myosin. In some types of muscle wasting diseases, such as Laing early onset distal myopathy, the part of the myosin that is important for making the thick filaments is mutated. We think this means that thick filaments do not form properly, causing the muscle wasting observed. Our research will shed light on this idea, to help us understand how myosin mutations result in muscle wasting. We will investigate the effects of the mutations on the structure of this part of the myosin, and determine how the mutations affect the ability of the myosin to integrate into thick filaments.