Uncovering mechanisms underlying the transdifferentiation of human muscle fibroblasts into adipocytes

骨骼肌是人体最大、最重要的组织之一。它不仅在允许我们移动和执行日常生活中所有必要的身体任务方面发挥着明显的功能，它还具有许多其他对健康至关重要的重要功能。这包括是体内葡萄糖摄取的最重要来源。然而，在许多情况下，肌肉会发生丢失和“质量”下降，肌肉内脂肪的积累和纤维化会损害收缩和代谢功能。这种情况尤其发生在虚弱的老年人的肌肉中。鉴于人们现在的寿命延长了，这导致受影响的人口急剧增加。此外，还有许多疾病，如肥胖症和2型糖尿病，以及一系列发生纤维脂肪堆积的肌肉疾病。然而，尽管流行，但影响这些变化的基本生物学过程仍然不清楚。我们最近证明，人类骨骼肌中的一群细胞，称为成纤维细胞(导致纤维化)，也是具有产生脂肪细胞和脂肪沉积能力的细胞。本申请中概述的工作旨在揭示推动成纤维细胞变成脂肪细胞过程的分子机制，以试图防止或改善纤维脂肪堆积。借助伦敦国王学院的生物医学研究人员和我们的合作工业合作伙伴葛兰素史克的专业知识，我们的具体目标是确定启动导致成纤维细胞转变为脂肪细胞的事件的分子；绘制成纤维细胞特性减弱和产生脂肪细胞的事件的图表；确定成纤维细胞是否活着并在体内产生脂肪细胞；以及表明如果你去除骨骼肌中的成纤维细胞，这是防止或损害脂肪积累的。为了实现这些目标，这笔赠款将人类细胞培养、细胞成像、RNA深度测序和活体工作中的最先进技术结合在一起。这是国王学院与葛兰素史克在肌肉生物学方面的专业知识的多学科合作，葛兰素史克有一个平行的研究项目，目标是肌肉老化和再生。这些实验的结果有望为骨骼肌中驱动细胞命运的机制提供新的见解，并有可能形成旨在防止肌肉中纤维脂肪替代的新治疗药物的基础。

Skeletal muscle is the largest and one of the most important tissues in the body. Not only does it perform obvious functions in allowing us to move and perform all the necessary physical tasks of daily living, it also has numerous other vital functions which are fundamental to health. These include being the most important source for the uptake of glucose in the body. However, there are numerous conditions where muscle loss occurs and "quality" declines, with the accumulation of intramuscular fat and fibrosis impairing both contractile and metabolic function. This occurs particularly in the muscles of frail elderly people. Given the fact that people are now living longer, this is resulting in a dramatically increasing population of people affected. Furthermore, there are also numerous diseases such as obesity and type 2 diabetes, as well a range of muscular diseases where fibro-fatty accumulation occurs. However, despite the prevalence the basic biological processes that influence these changes remain unclear. We have recently demonstrated that a population of cells resident within human skeletal muscle, called "fibroblasts" (which give rise to fibrosis), are also the cells that have the capability of giving rise to fat cells and fatty deposits.. The work outlined in this application is targeted at uncovering the molecular mechanisms which drive the process of a fibroblast to become a fat cell, in order to try to prevent or ameliorate fibro-fatty accumulation. With the combined expertise of biomedical researchers at King's College London and GSK, our collaborating industrial partner, we specifically aim to identify the molecules that initiate the events that cause a fibroblast to change into a fat cell; to chart the events that underlie the waning of the fibroblast characteristics and the waxing of those events that produce a fat cell; determine if the fibroblasts are viable and give rise to fat cells in vivo; and show that if you ablate the fibroblasts in skeletal muscle whether this prevents or impairs the fatty accumulation. To achieve these aims this grant brings together state-of-the-art techniques in human cell culture, cell imaging, RNAdeep sequencing, and in vivo work. It is a multidisciplinary collaboration of expertise in muscle biology at King's College with GlaxoSmithKline who have a parallel research programme targeted at muscle ageing and regeneration. The results of these experiments promise new insights into the mechanisms driving cell fate in skeletal muscle and have the potential to form the basis of new therapeutic agents directed at preventing fibro-fatty replacement in muscle.