MICA: Determining how mutations in myosin cause skeletal muscle disease

骨骼肌约占人体的40%。毫不奇怪，有很多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，它是由一种叫做肌凝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，它们的末端是肌肉肌腱。肌肉纤维是由成千上万的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形成的。在肌纤维中，两种主要的蛋白质相互作用使肌纤维变短，它们被组织成一种高度规则的重复单元，称为肌节。这些纤维端到端被组织成叫做肌原纤维的长结构，从纤维的一端延伸到另一端。一根纤维充满了肌原纤维，约占纤维总体积的80%。一根纤维大约有200毫米长，而一个肌节只有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，肌凝蛋白被组织成粗丝，肌动蛋白在它们之间被组织成细丝。当肌肉收缩时，粗纤维中的肌凝蛋白与细纤维中的肌动蛋白相互作用。这些牵拉着细丝，导致每个肌节缩短约10%。每个肌节内的每一个小运动都沿着肌纤维汇总，在其末端产生更大的运动，使肌肉能够运动关节。为了使这一切起作用，肌凝蛋白必须精确地组织成粗丝。事实上，每根粗丝含有294个肌凝蛋白分子。在某些类型的肌肉萎缩疾病中，如Laing早发性远端肌病，对形成粗纤维很重要的肌球蛋白部分发生突变。我们认为这意味着粗纤维不能正常形成，导致观察到的肌肉萎缩。我们的研究将阐明这个观点，帮助我们理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凝蛋白这部分结构的影响，并确定突变如何影响肌凝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.