Abstract/Summary

Ageing, defined as the progressive deterioration of molecular, cellular, tissue and whole organism function, is a primary risk factor for numerous diseases, such as cardiovasculature disease, neurodegeneration and cancer. In recent years, advances in our knowledge of key determinant mechanisms that underpin ageing decline, drives the notion that these features can be attenuated and targeted therapeutically, enabling elderly individuals to experience an enhanced quality of life into advanced old age. Sarcopenia comprises the age-­‐related loss of muscle mass, quality and function and contributes to overall frailty, immobility and a greater risk of falls. The use of stem cell-­‐ derived conditioned media (CM) holds great clinical potential and recent studies have reported many beneficial effects in a number of tissue models of injury and disease. We want to develop a novel anti-­‐ageing therapy for the treatment of age-­‐associated declines in sarcopenia. First, we characterise the skeletal muscle profile in a novel use of the Ercc1d/-­‐ murine model of progeria and compare it to the naturally-­‐aged phenotype. We examine the effects of CM, generated from adipose-­‐derived mesenchymal stem cells (ADMSCs), on skeletal muscle composition, function and satellite cell (SC) activity in sarcopenia and progeria. We show that CM has beneficial regulatory effects on mechanisms underpinning the declines associated with the Hallmarks of Ageing, for example, enhancing mitochondrial function and reducing oxidative stress. Importantly, we also demonstrate that CM harbours pro-­‐angiogenic effects, which we hypothesise is unlikely to impact on skeletal muscle alone. Remarkably, we report the Ercc1d/-­‐ mice appear to launch a survival programme and delay the progression of age-­‐related deterioration. A further feature associated with ageing skeletal muscle is the impaired regenerative function and myofibre turnover following injury and daily use. Key factors attributed to this decline in repair involve compromised SC activity as well as the depletion of the stem cell pool, known to occur with age. We want to first, examine the influence of the myofibre microenvironment on SC behaviour. Second, we investigate the use of non-­‐muscle cell types as a source to generate muscle cells. We show that three stem cell types, ADMSC, dental pulp stem cells (DP) and amniotic fluid stem cells (AFS) and one non-­‐stem cell line, MDA-­‐MB-­‐231 (MDA) breast cancer cells, adopted amoeboid-­‐based migration (blebbing) once seeded onto myofibres. We also show that the regulation of the migratory mechanisms, known to be controlled by the Rac and Rho signalling pathways, is conserved in each of these cell types. Remarkably, we also demonstrate that a rapidly growing non-­‐muscle stem cell (AFS), as well as a non-­‐stem cell (MDA) initiate expression of MyoD and furthermore, the AFS cells were directed, through exposure to the myofibre microenvironment, to fuse and form myotube structures that express myosin heavy chain (MHC+).