Pathomechanisms in Facioscapulohumeral muscular dystrophy

如果知道症状背后的原因/机制，就能更有效地治疗疾病。对于肌肉萎缩症来说，致病缺陷是基因或DNA的变化，而基因或DNA的变化又会导致蛋白质的变化。然而，人们通常不太了解这些缺陷是如何导致衰弱的，进行性骨骼肌无力和肌肉萎缩症典型的消瘦。人体内的每个细胞都含有相同的DNA，这些DNA被分成基因，每个基因都携带着制造蛋白质的指令：蛋白质是构建、维持和运作身体的分子。在特定细胞类型（如肌肉纤维）中表达（活跃）的基因的选择决定了蛋白质的产生。这赋予了细胞特殊的特性和功能。例如，特定的肌肉基因不会在皮肤细胞中表达，反之亦然。面肩肱肌营养不良症（FSHD）是无法治愈的。FSHD是由DNA特定区域的变化引起的，这种变化会导致一种叫做DUX4的蛋白质的产生，这种蛋白质通常不存在于肌肉中。DUX4是一种“转录因子”，这意味着它可以通过与其他基因的调控区域结合来控制它们的表达，因此可以改变细胞产生的蛋白质的类型。因此，使骨骼肌有效运作的基因表达和蛋白质产生的精心协调的模式被DUX4的存在扰乱了。这最终会导致肌肉无力和消瘦。我们检测了表达FSHD和dux4的肌肉细胞的基因表达变化，并使用数学工具来了解哪些信号过程受到干扰。我们发现，控制线粒体生成和与线粒体功能相关的过程的途径被抑制，例如处理代谢/呼吸的副产物，称为活性氧（引起氧化应激）。众所周知，FSHD肌肉细胞对氧化应激更敏感，最近的一项临床试验（clinicaltrials.gov编号：NCT01596803）报告称，抗氧化剂的使用改善了FSHD患者的肌肉功能。肌肉代谢是精心协调的，以确保产生足够的能量，使肌肉始终有效地工作，从休息到进行剧烈运动。这些系统在FSHD中受到干扰，但尚不清楚DUX4是如何做到这一点的。为了进行研究，我们将检查FSHD细胞和用于表达DUX4的细胞的代谢率（使用称为呼吸测量的技术），基因表达的变化（使用称为rna测序的技术）和代谢（使用称为核磁共振（NMR）的技术）。这将使我们更好地了解FSHD的病因，长期目标是为FSHD找到新的、更有效的靶向治疗方法，为临床试验提供信息、支持和基础。

Diseases can be treated more effectively if the causes/mechanisms underlying the symptoms are known. For muscular dystrophy, the causative defect is changes in genes or DNA that in turn, produce changes to proteins. However, it is generally poorly understood how such defects result in the debilitating, progressive skeletal muscle weakness and wasting typical of muscular dystrophies. Every cell in the body contains the same DNA, which is divided into genes, each of which carries the instructions to make a protein(s): the molecules that build, maintain and operate the body. The selection of genes that are expressed (active) in a particular cell type, such as in a muscle fibre, dictate which proteins are made. This gives the cell its special characteristics and functions. For example, specific muscle genes are not expressed in skin cells, and vice-versa.Facioscapulohumeral muscular dystrophy (FSHD) is incurable. FSHD is caused by a change in a particular region of DNA that leads to production of a protein called DUX4, that is not normally present in muscle. DUX4 is a 'transcription factor' meaning that it can control the expression of other genes by binding to their regulatory regions, and so can alter the type of proteins that are made by a cell. Thus the carefully coordinated pattern of gene expression and protein production that enables skeletal muscle to function effectively is perturbed by the presence of DUX4. This ultimately leads to muscle weakness and wasting.We have examined gene expression changes in FSHD and DUX4-expressing muscle cells and used mathematical tools to understand which signalling process are perturbed. We found that pathways are suppressed that control generation of mitochondria and processes associated with mitochondrial function such as dealing with by-products of metabolism/respiration called reactive oxygen species (that cause oxidative stress). It is known that FSHD muscle cells are more sensitive to oxidative stress, and a recent clinical trial (clinicaltrials.gov number: NCT01596803) reported that administration of anti-oxidants, improved aspects of muscle function in FSHD patients.Muscle metabolism is carefully coordinated to ensure generation of enough energy to make muscle always work efficiently, from when resting to undergoing strenuous exercise. These systems are perturbed in FSHD but it is unclear how DUX4 does this. To investigate, we will examine the rate of metabolism (using a technique called respirometry), changes in gene expression (using a technique called RNA-Sequencing) and metabolism (using a technique called Nuclear magnetic resonance (NMR)) in FSHD cells and cells made to express DUX4. This will give a better understanding of the cause of FSHD, with the long-term aim of finding new and more effective targeted therapies for FSHD to inform, support and underpin clinical trials.