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

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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.