Understanding age-related changes in skeletal muscle protein turnover in response to exercise, nutrition and pharmacological interventions.

该项目以两个关键主题为基础，这两个主题与健康老龄化主题密切相关。首先，推进我们对随着年龄增长而导致肌肉损失的代谢机制的理解。第二，发现新的干预措施来对抗随着年龄增长的肌肉损失。肌肉减少症定义为年龄相关的骨骼肌质量和功能下降，被认为是一种独立的老年疾病，有自己的国际疾病分类[Cao and莫利，2016 J Am Med Dir Asynchronous]。这种临床状况早在生命的第40个十年开始，并导致发病率和死亡率的风险增加。骨骼肌减少症的一个根本原因是骨骼肌蛋白质的部分合成速率响应于身体活动和营养随年龄增长而受损。这种现象被称为肌肉合成代谢抵抗，并已在整体肌肉水平上得到广泛表征，即当所有类型的肌肉蛋白（肌原纤维蛋白、线粒体蛋白和肌浆蛋白）的合成速率结合时[摩尔，Churchward-Venne，Witard等人，2015 J Gerontol A Biol Sci Med Sci]。横断面研究表明，在大多数情况下，老年人与年轻人相比，急性餐后期间整体肌肉蛋白合成率较低[Cuthberton et al. 2005 FASEB]。相反，关于个体功能不同（即肌动蛋白、肌球蛋白、原肌球蛋白、肌钙蛋白等）的合成速率的年龄相关变化的信息有限。肌肉蛋白[Shankaran et al. 2016 Am J Phys]。这种详细程度对于（a）促进对支撑（肌肉骨骼）老化过程的生物学机制的理解和（B）确定对抗肌肉减少症的有针对性的干预措施至关重要。该项目将提供迄今为止对整个生命过程中肌肉蛋白质合成率与年龄相关变化的最全面评估。因此，该项目分为三个基于实验室的研究。研究1基于湿实验室，重点是优化蛋白质组学技术，用于体内测量单个肌肉蛋白的分数合成率。我们将利用KCL质谱卓越中心的蛋白质组学实验室对先前收集的[Shad et al. Int J Sp Nutr Ex Metab]氧化氘标记的人体肌肉组织样本进行这些测量。研究2将采用横断面研究设计，直接比较年轻人、中年人和老年人之间个体肌肉蛋白的合成率。在与马斯特里赫特大学的合作中，氧化氘示踪方法将与蛋白质组学技术相结合，以进行这些测量。这些数据将用于确定新的干预措施，旨在减轻个体肌肉蛋白合成率的年龄相关变化，因此，将为研究3提供指导。研究3将采用与研究2相同的方法，但引入了一种新的药理学/非药理学干预措施，旨在减轻个体蛋白质水平下肌肉蛋白质合成速率的变化。 研究目的：优化最先进的氧化氘同位素示踪方法和蛋白质组学技术，以测量年轻人，中年人和老年人之间的整体和个体肌肉蛋白质的合成率。确定年轻人、中年人和老年人之间整体和个体肌肉蛋白质合成率的变化。研究药物（senolytics）或非药物（蛋白质喂养模式，亮氨酸补充剂）干预在整个生命过程中调节整体和个体肌肉蛋白质合成速率变化的影响。

This project is underpinned by two key themes prudent to the topic of healthy ageing. First, advancing our understanding of the metabolic mechanisms that underpin muscle loss with ageing. Second, the discovery of novel interventions to combat muscle loss with ageing. Sarcopenia is defined as the age-related decline in skeletal muscle mass and function and is recognised as an independent geriatric condition with its own International Classification of disease [Cao and Morley, 2016 J Am Med Dir Assoc]. This clinical condition begins as early as the 4th decade of life and leads to increased risks of morbidity and mortality. A fundamental cause of sarcopenia is an impairment in fractional synthesis rates of skeletal muscle proteins in response to physical activity and nutrition with ageing. This phenomenon is termed muscle anabolic resistance and has been extensively characterised on a global muscle level, i.e. when the synthesis rates of all types of muscle protein (myofibrillar, mitochondrial and sarcoplasmic proteins) are combined [Moore, Churchward-Venne, Witard et al. 2015 J Gerontol A Biol Sci Med Sci]. Cross-sectional studies demonstrate that, for the most part, lower global muscle protein synthesis rates during the acute postprandial period are evident in older vs. young adults [Cuthberton et al. 2005 FASEB]. In contrast, limited information exists regarding age-related changes in synthesis rates of individual, functionally distinct (i.e. actin, myosin, tropomyosin, troponin, etc.) muscle proteins [Shankaran et al. 2016 Am J Phys]. This level of detail is critical to (a) advancing understanding of the biological mechanisms that underpin the (musculoskeletal) ageing process and (b) identifying targeted interventions to counteract sarcopenia. This project will deliver, to date, the most comprehensive assessment of age-related changes in synthesis rates of muscle proteins across the lifecourse. Accordingly, the project is split into three laboratory-based studies. Study 1 is based in the wet-lab and is focussed on optimising the proteomics technology for the in vivo measurement of fractional synthesis rates of individual muscle proteins. We will utilise the proteomics laboratory in the Centre of Excellence for Mass Spectrometry at KCL to conduct these measurements on previously collected [Shad et al. Int J Sp Nutr Ex Metab] deuterium oxide labelled human muscle tissue samples. Study 2 will utilise a cross-sectional research design to directly compare fractional synthesis rates of individual muscle proteins between young, middle-aged and older adults. In collaboration with Maastricht University, the deuterium oxide tracer method will be combined with proteomics technology to conduct these measurements. These data will be used to identify novel interventions targeted at mitigating age-related changes in synthesis rates of individual muscle proteins and, as such, will inform the direction of study 3. Study 3 will utilise the same methodology as study 2 but introduce a novel pharmacological/non-pharmacological intervention targeted at mitigating changes in muscle protein synthesis rates at the individual protein level. Aim of the investigation: To optimise state-of-the-art deuterium oxide isotope tracer methodology and proteomics technology to measure synthesis rates of global and individual muscle proteins between young, middle-aged, and older adults. To determine changes in synthesis rates of global and individual muscle proteins between young, middle-aged, and older adults. To investigate the influence of pharmacological (senolytics) or non-pharmacological (protein feeding pattern, leucine supplementation) interventions in modulating changes in synthesis rates of global and individual muscle proteins across the lifecourse.