Differential impact of anabolic and catabolic stimuli on differentiation of young and old murine and human myoblasts

Elbouzidi, Aisha (2017) Differential impact of anabolic and catabolic stimuli on differentiation of young and old murine and human myoblasts. Masters by Research thesis (MPhil), Manchester Metropolitan University.

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Abstract

Although it is important to understand the molecular mechanisms underpinning muscle wasting with aging, it is ultimately the failure of cell function that leads to all aging phenomena. Part of the cause of cellular dysfunction in old age is thought to be chronic, low grade, systemic inflammation in the face of reduced anabolic drives. Skeletal muscle and its resident stem cells provide good models of cellular and tissue failure with age. Easy access to muscle-derived stem cells provides a tool with which to assess local vs. environmental triggers of age-related cellular dysfunction. The aim of this study was to develop relevant models of age-related muscle wasting. The hypothesis was that older muscle cells would be more prone to catabolic and less prone to anabolic adaptation vs. younger muscle cells. Objectives were to compare and contrast younger and older skeletal muscle cell adaptation to anabolic (IGF-I) and catabolic (IL-6 and TNF-α) stimuli. In the murine model, and in line with expectations, IGF-I (100 ng/ml) resulted in improved fusion in younger, but reduced fusion in older myoblasts. By contrast, and unexpectedly, in human myoblasts the opposite occurred, where IGF-I (100 ng/ml) resulted in reduced fusion in younger, but increased fusion in older myoblasts. Where improved fusion was evident (regardless of model or age) with IGF-I administration, this was associated with enhanced basal fusion potential, which should therefore be considered when choosing models of study. It is currently not known what drives altered basal fusion capability and the subsequent enhanced response to IGF-I. Therefore, the two models together provide an opportunity to further investigate this finding. When assessing the impact of catabolic cytokines on myoblast fusion, both models displayed increased negative adaptation in older vs. younger myoblasts. However, and interestingly, older murine myoblasts were more responsive to TNF-α and older human myoblasts to IL-6 administration. The impaired differentiation in response to the cytokines may underlie the muscle wasting evident in older age, and again provides a good model of study. In conclusion, evidence is provided here of the development of muscle models for investigating muscle aging in vitro. Early data suggest that care should be taken when choosing the model and this should be driven by the final question being addressed e.g., the model for studying hypertrophy may not be the best model for studying atrophy.