REBUILD · Mechanisms of sarcomeric protein homeostasis during physical exercise and ageing

Mechanisms of sarcomeric protein homeostasis during physical exercise and ageing

During ageing muscle fibers are constantly subjected to high forces resulting in mechanical stress on cells and proteins. As a consequence, they can degenerate, leading to suboptimal force generation, lack of coordinated movements and ultimately to muscle failure in the elderly population. This ageing process that leads to a progressive loss of muscle function has a major health impact on the ageing Western society. Physical activity is known to delay this decline. The REBUILD project aims to determine the temporal dynamics of protein replacement during life of a muscle fiber by SILAC-based mass spectrometry and genetics. It integrates biomechanics with muscle homeostasis and accurately quantify the impact of physical activity on protein turnover and investigate the physiological consequences for the ageing animal. By combining the power of genetics and SILAC-based proteomics with behaviour of free flight under defined exercise conditions, we create a unique position for a discovery orientated large-scale in vivo genetic screen. We determined the temporal dynamics of protein replacement during the life of flight muscle fibers in Drosophila by SILAC-based mass spectrometry. Protein replacement is assessed by incorporation of heavy Lys8 in newly synthetized proteins, allowing us to obtain turnover rates for the entire proteome in an unbiased manner. By employing a newly designed Flydome, an apparatus to induce Drosophila flight on demand, together with animals incapable of flight-muscle contraction we quantify the impact of muscle contraction on protein turnover rates and investigate the physiological consequences for the ageing subject. Our initial analysis reveals a surprisingly low turnover of sarcomeric and structural proteins in adult animals, that might be a reflection on the high density and stability of muscle fibers. Nevertheless, a subset of these sarcomeric muscle components turns over at higher rates, which is surprising due to their “core sarcomeric” nature. Further validation studies are now due as well as the study of the mechanisms behind this protein turnover. A precise understanding of mechanisms that control homeostatic replacement of damaged proteins in muscle fibers should foster interventions aimed at maintenance of muscle capacity in older individuals and thus, an important step towards healthy ageing.

Текст от CORDIS, на английски · Данни: CORDIS, © Европейски съюз