Exploring metabolic and molecular mechanisms regulating age-related declines in human skeletal muscle regenerative capacity.

Abstract

The underlying mechanisms regulating the ability of skeletal muscle to regenerate after acute “damaging” eccentric or “non-damaging” concentric exercise in young human skeletal muscle is poorly defined. Age-related impairments in the regenerative mechanisms may contribute to the age-related loss of muscle mass and function, which has negative consequences for overall health and disease. Thus, the first aim of this thesis was to initially investigate multiple targeted mechanisms previously implicated in the regeneration process, over a comprehensive time-course following eccentric versus concentric exercise in young adults. Within this study it was found that post-exercise, in general, increased anabolic and repressed catabolic signalling preceded functional decline, whereas inflammation and ubiquitin proteasome system-related breakdown increased once functional recovery was initiated/achieved. Eccentric exercise led to greater anabolic signalling and inflammatory signalling response. As such, this study has provided a benchmark of muscle regeneration in young skeletal muscle, which implicates early anabolic and catabolic regulation in the rapid adaptation of muscle, whereas inflammation and ubiquitin proteasome system-related breakdown likely mediate longer term remodelling/adaptations, which may be greater following eccentric exercise. Using this benchmark, the aim of the second study was to identify age-related changes in targeted regenerative mechanisms. Concentric exercise did not cause a molecular regenerative response, whilst eccentric exercise induced anabolic signalling and satellite cell activation, prior to and at the nadir of force, respectively. Compared to the younger adults, ageing per se was associated with increased inflammation, whilst anabolic and catabolic signalling post-eccentric and concentric exercise was blunted. Interestingly, satellite cell activity was induced in the old only following eccentric exercise. These data suggest that eccentric exercise is potentially more advantageous for promoting muscle growth versus concentric exercise in older adults. Whilst, compared to the young, the old displayed blunted molecular responses which might underlie blunted muscle growth during ageing. Furthermore, the activation of satellite cells in the old might be the result of the impaired molecular mechanisms being suboptimal for repair thus, requiring additional regenerative means. In order to further characterise ageing muscle and the mechanisms of muscle regeneration, RNA sequencing was performed at the time of peak anabolic signalling to highlight more global and novel molecular networks. Ageing per se revealed genes involved in blood vessel development, plasma membrane and cell-cell junction expression were down-regulated, thus implicating these processes in age-related muscle loss. Following concentric exercise in older adults, there was an up-regulation of structural transcripts whilst there was a general down-regulation of genes related to metabolism, which might suggest impaired metabolism post-concentric exercise. Perhaps the blunted transcript responses contribute to the often observed age-related blunting of muscle mass adaptations in response to exercise training. Collectively, the data from this thesis has important implications for developing interventions for maximising hypertrophic responses and for counteracting the suboptimal regenerative responses observed in older adults.