Molecular transducers of exercise training adaptations in young and aged skeletal muscle

Besides neurodegeneration, musculoskeletal weakness is the main cause for the loss of independence and nursing home placement in elderly individuals. The high morbidity, mortality and costs associated with functional degeneration and linked comorbidities are a major threat to healthcare systems and society. Exercise training, even when applied later in life, is the single most effective intervention to preserve and/or improve muscle function and cardiovascular deficits but also shows significant benefits in preventing and/or treating neurodegenerative disorders and other diseases related to a sedentary life style or aging. However, the molecular mechanisms underlying the potent effect of exercise are still poorly understood. Consequently, alternative treatment options for partially or fully exercise intolerant populations or individuals unwilling to exercise are lacking. The overarching goal of this thesis was to improve the mechanistic understanding of exercise training adaptation to foster the development of novel pharmacological and/or exercise-based therapies to preserve and/or enhance cardiovascular and muscle function. First, the potential of recombinant IL-6 to act as a therapeutic agent for the treatment and/or prevention of age-related frailty was tested in old mice. Second, a comprehensive characterization of the systemic and muscle-specific adaptations to voluntary low-load (Run) and progressive resistance (RR) wheel running in young mice was performed. Third, an innovative tool to study the mechanisms by which PGC-1α mediates endurance exercise adaptions in skeletal muscle in vivo was finalized, validated and applied. IL-6 combined with exercise bouts potentiated the adaptive response of skeletal muscle to endurance training, characterized by superior fatigue resistance. In sedentary mice, IL-6 had only minor effects on the assessed outcome measures. However, the treatment appeared to be safe and well tolerated in both trained and untrained animals. Both wheel running-based training modalities increased V̇O2peak, while Run more strongly improved submaximal running performance compared to RR. Conversely, only RR induced gains in grip strength and more effectively increased M. soleus mass, most likely via connective tissue and/or extracellular matrix remodeling. The PGC-1α1 protein-interactome was found to massively expand and change its composition in response to a single bout of exhaustive treadmill running in a time-dependent manner. In addition, a series of experiments indicated that the exact expression pattern of the alternative promoter has to be clarified, in particular regarding the independent expression of the alternative first exons E1b and E1c. Finally, besides potential shorter isoforms, our results suggested that a large amount of PGC-1α that arises from the alternative promoter following exercise is the full-length variant. The observed effects of IL-6 treatment point towards a direct role of the systemic increase of this myokine in training adaptation, at least in older mice. If these results can be translated to elderly individuals, IL-6 treatment could not only improve training interventions, and hence increase adherence and compliance, but also directly result in massive improvement of quality of life. This would be of great value to overcome one of the biggest challenges of exercise-based interventions in elderly populations – the reduced training response or even exercise intolerance. We conclude that RR provides a hybrid stimulus of endurance- and resistance-exercise components and thereby elicits the complete spectrum of structural, functional and metabolic training adaptations. RR could therefore be used as translational model for concurrent training in humans. Moreover, collective data from this study will facilitate training model selection for exercise and muscle researchers and thereby help to elucidate the mechanisms underlying exercise training adaptation. Investigation of targets emerging from the protein-interactome data set and additional future experiments enabled by the PGC-1α1 tagged mouse will advance our understanding of how this coregulator protein mediates an endurance-training phenotype