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，这两个主题是关于健康老龄化的审慎主题。首先，促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，发现了新的干预措施来对抗随着年龄增长而导致的肌肉损失。骨质疏松症被定义为与年龄相关的骨骼肌质量和功能下降，并被认为是一种独立的老年疾病，有自己的国际疾病分类[CaO和Morley，2016年医学杂志Assoc]。这种临床情况早在生命的第四个十年就开始了，并导致发病率和死亡率增加的风险。骨骼肌减少的一个根本原因是随着年龄的增长，骨骼肌蛋白质对体力活动和营养的反应的部分合成率受损。这种现象被称为肌肉合成代谢抵抗，在全球肌肉水平上被广泛描述，即当所有类型的肌肉蛋白质(肌原纤维、线粒体和肌浆蛋白质)的合成速率结合在一起时[Moore，Churchward-Venne，Witard等人。2015 J Gerontol A Biol Sci Med Sci[J Gerontol A Biol Sci Med Sci]横断面研究表明，在大多数情况下，在急性餐后时期，老年人与年轻人相比，全球肌肉蛋白质合成率较低是明显的[Cuthberton等人。2005 FASE B]。相比之下，关于个体功能不同(如肌动蛋白、肌球蛋白、原肌球蛋白、肌钙蛋白等)合成率随年龄变化的信息有限。肌肉蛋白质[Shankaran等人。2016年上午[J Phys]。这一详细程度对于(A)促进对支撑(肌肉骨骼)衰老过程的生物学机制的了解和(B)确定有针对性的干预措施以对抗骨质疏松症至关重要。到目前为止，该项目将对整个生命过程中肌肉蛋白质合成速率随年龄的变化进行最全面的评估。因此，该项目被分成三个基于实验室的研究。研究1以湿法实验室为基础，专注于优化蛋白质组学技术，用于体内测量单个肌肉蛋白质的部分合成速率。我们将利用KCL质谱学卓越中心的蛋白质组实验室对以前收集的数据进行这些测量[Shad等人。访问数/每百万人：Reach for[InJ Sp Nutr Ex Metab]研究2将利用横断面研究设计，直接比较年轻人、中年人和老年人个体肌肉蛋白质的部分合成率。在与马斯特里赫特大学的合作下，氧化氢示踪法将与蛋白质组学技术相结合来进行这些测量。这些数据将被用来确定新的干预措施，以减轻个体肌肉蛋白质合成速率随年龄的变化，并因此为研究3的方向提供指导。研究3将使用与研究2相同的方法，但引入一种新的药理/非药物干预措施，目标是在个体蛋白质水平上缓解肌肉蛋白质合成速率的变化。研究目的：优化最先进的氧化氢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全球和单个肌肉蛋白质的合成速度。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。研究药理(感觉剂)或非药理(蛋白质喂养方式、亮氨酸补充)干预对调节整个生命周期内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.