Characterization of transcriptional modulators involved in exercise-induced adaptive remodeling of skeletal muscle

Regular exercise is a cornerstone of health and longevity, especially in a society marked by increasing age and sedentary behavior. Skeletal muscle, the primary organ for locomotion, exhibits extraordinary plasticity, with the ability to adapt to repeated perturbations such as exercise. Adaptive remodeling of skeletal muscle in response to endurance exercise induces a series of changes in the tissue encompassing elevated metabolic capacity, mitochondrial content and vascularization. These adaptive mechanisms are predicated on the perturbation of cellular homeostasis during the individual exercise bout. The muscle senses these perturbations and reacts with a transcriptional network, unfolding in the hours post-exercise. This exercise-induced response encompasses the blueprint for short-term reestablishment of cellular homeostasis and long-term adaptive remodeling of skeletal muscle. Elucidating this intricate network and characterizing its key players contributes to our comprehension of what constitutes healthy muscle and holds potential for new therapeutic avenues treating conditions caused by a sedentary lifestyle. This dissertation advances our understanding of two key regulators within this network – the transcription factor Krüppel-like factor 5 (Klf5) and the transcriptional coactivator peroxisome proliferator-activated receptor-gamma coactivator 1alpha (PGC-1α). We identified Klf5 as a crucial regulator of the adaptive remodeling of lipid metabolism within muscle in response to exercise – a fundamental process to increase endurance-exercise performance and metabolic health. For PGC-1α, a rather well researched player in the adaptive remodeling of skeletal muscle, we deliver a comprehensive overview of the isoforms induced by endurance exercise, identifying novel PGC-1α-variants, providing further insight into the regulation of this focal player of exercise adaptation. This thesis thus provides insights into the molecular regulators governing adaptive remodeling of skeletal muscle.