MICA: Determining how mutations in myosin cause skeletal muscle disease

MICA：确定肌球蛋白突变如何导致骨骼肌疾病

• 批准号: MR/K001272/1
• 负责人: Michelle Peckham
• 金额: $ 41.84万
• 依托单位: University of Leeds
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2013
• 资助国家: 英国
• 起止时间: 2013 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=MR%2FK001272%2F1
• 关键词: MICA; Determining; how; mutations; myosin

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.

骨骼肌约占人体的40%。毫不奇怪，有很多疾病会影响肌肉的结构和功能。其中之一是一种肌肉萎缩性疾病，它是由一种叫做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，它们在肌腱中结束。肌肉纤维是由成千上万的细胞融合在一起形成一个单一的巨细胞，包含数千个细胞核。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，它们被组织成一种高度规则的重复单元，称为肌肉肌节。这些组织首尾相连，形成称为肌原纤维的长结构，从纤维的一端延伸到另一端。单根纤维充满了肌原纤维，约占纤维总体积的80%。单个纤维可以是大约200 mm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有大约100，000个肌节。在每个肌节内，肌球蛋白被组织成粗丝，在它们之间，肌动蛋白被组织成细丝。当肌肉收缩时，粗肌丝中肌球蛋白的突起（横桥）与细肌丝中的肌动蛋白相互作用。这些拉力作用于细肌丝，导致每个肌节缩短约10%。每个肌节内的这些小运动中的每一个都沿着肌肉纤维相加，以在其末端产生更大的运动，从而使肌肉能够运动关节。为了使所有这些都发挥作用，肌球蛋白必须精确地组织成粗丝。事实上，每一根粗肌丝恰好含有294个肌球蛋白分子。在某些类型的肌肉萎缩性疾病中，如Laing早发性远端肌病，肌球蛋白中对制造粗肌丝很重要的部分发生突变。我们认为这意味着粗丝不能正常形成，导致观察到的肌肉萎缩。我们的研究将阐明这一想法，帮助我们了解肌球蛋白突变如何导致肌肉萎缩。我们将研究突变对这部分肌球蛋白结构的影响，并确定突变如何影响肌球蛋白整合成粗丝的能力。

项目成果

Promoting differentiation of cultured myoblasts using biomimetic surfaces that present alpha-laminin-2 peptides.

• DOI: 10.1007/s10616-016-0006-y
• 发表时间: 2016-10
• 期刊: Cytotechnology
• 影响因子: 2.2
• 作者: Parker F;White K;Phillips S;Peckham M
• 通讯作者: Peckham M

Unravelling the Properties of Single a-Helical Domains in Myosin and other Proteins

揭示肌球蛋白和其他蛋白质中单个α螺旋结构域的特性

• DOI: 10.1016/j.bpj.2013.11.3459
• 发表时间: 2014
• 期刊: Biophysical Journal
• 影响因子: 3.4
• 作者: Wolny M