Uncovering mechanisms underlying the transdifferentiation of human muscle fibroblasts into adipocytes

骨骼肌是人体最大的组织，也是最重要的组织之一。它不仅具有明显的功能，使我们能够移动和执行日常生活中所有必要的身体任务，它还具有许多其他对健康至关重要的重要功能。这些包括成为体内摄取葡萄糖的最重要来源。然而，有许多情况下，肌肉损失发生和“质量”下降，肌内脂肪的积累和纤维化损害收缩和代谢功能。这种情况尤其发生在年老体弱的人的肌肉中。鉴于人们现在的寿命更长，这导致受影响的人口急剧增加。此外，还有许多疾病，如肥胖和2型糖尿病，以及一系列肌肉疾病，其中纤维脂肪积累发生。然而，尽管流行，影响这些变化的基本生物过程仍然不清楚。我们最近已经证明，人类骨骼肌内的一群细胞，称为“成纤维细胞”（引起纤维化），也是具有引起脂肪细胞和脂肪沉积的能力的细胞。本申请中概述的工作旨在揭示驱动成纤维细胞变成脂肪细胞的分子机制，以尝试预防或改善纤维脂肪积累。结合伦敦国王学院和我们的工业合作伙伴GSK的生物医学研究人员的专业知识，我们的目标是确定引发导致成纤维细胞转变为脂肪细胞的事件的分子;绘制成纤维细胞特征减弱和产生脂肪细胞的事件的基础事件;确定成纤维细胞是否有活力并在体内产生脂肪细胞;并表明如果你消融骨骼肌中的成纤维细胞，这是否会阻止或削弱脂肪积累。为了实现这些目标，该资助汇集了人类细胞培养，细胞成像，RNAdeep测序和体内工作的最先进技术。这是国王学院与葛兰素史克公司在肌肉生物学方面的专业知识的多学科合作，葛兰素史克公司有一个针对肌肉老化和再生的平行研究计划。这些实验的结果有望对骨骼肌中驱动细胞命运的机制有新的见解，并有可能形成新的治疗药物的基础，这些药物旨在预防肌肉中的纤维脂肪替代。

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.