The role of adipose-derived extracellular vesicles in driving the impairment in skeletal muscle metabolic function and growth with ageing and obesity

肌肉质量和功能的下降(肌肉量减少)以及随着年龄的增长而增加的肥胖症是一项重大的医疗挑战，导致虚弱和慢性炎症性代谢疾病的发展，包括II型糖尿病(T2D)。肌内和肌内脂肪的积累加剧了胰岛素敏感性和肌肉质量的损害。重要的是，我们已经报道，肥胖(但不是正常体重)脂肪组织将人类肌肉暴露在分泌体中会损害肌肉生长，特别是在老年人中，这表明肥胖脂肪组织和肌肉之间的病理性串扰在石棺减少症的恶化中发挥了核心作用。随着最近发现细胞外小泡(EVS)作为细胞串扰的中介，能够运输包括小非编码RNA在内的货物，我们假设随着年龄的增长，肥胖脂肪组织释放病理性EVS，从而损害肌肉生长和肌肉代谢功能。这个奖学金的目的有两个。首先，确定这些来自瘦和肥胖个体的脂肪EV的小RNA货物的特征；其次，确定脂肪EV对肌肉生长和功能的影响，以确定用于治疗骨质疏松症的候选途径和药物靶点。

The decline in muscle mass and function (sarcopenia) and accompanying increase in adiposity with ageing is a major healthcare challenge, that drives frailty and the development of chronic inflammatory metabolic disorders including Type II Diabetes (T2D). The accumulation of intramuscular and intramyocellular fat exacerbates both the impairment of insulin sensitivity and muscle mass. Importantly, we have reported that exposure of human muscle to the secretome from obese (but not normal-weight) adipose tissue impairs muscle growth, particularly in elderly individuals, suggesting that pathological cross-talk between obese adipose tissue and muscle plays a central role in the exacerbation of sarcopenia.With the recent discovery of extracellular vesicles (EVs) as mediators of cellular cross-talk, capable of transporting cargo including small non-coding RNAs, we hypothesise that with ageing, obese adipose tissue releases pathological EVs that impair muscle growth and muscle metabolic function. The aim of this studentship is two-fold. Firstly, to characterise the small RNA cargo of these adipose EVs from lean and obese individuals, and secondly to determine the effect of adipose EVs on muscle growth and function to identify candidate pathways and drug targets for the development of therapeutics to combat sarcopenia.