MITOCHONDRIAL MEMORY AT SKELETAL MUSCLE LEVEL

Mitochondria are key components of skeletal muscles as they provide the energy required for almost all cellular activities. Different forms of exercise training have been associated with mitochondrial adaptations, such as increased mitochondrial content and function, and enhanced mitochondrial biogenesis, as well as improved endurance performance. High-intensity interval training and sprint interval training have been demonstrated to be the most effective training modalities to induce mitochondrial adaptations. However, surprisingly, greater changes in mitochondrial content and biogenesis were also observed after repeated resistance training interventions separated by prolonged detraining. This mechanism, defined muscle memory, has been well established for hypertrophy and skeletal muscle growth in response to resistance training and it has been related to the retention of acquired myonuclei or epigenetic modifications. Thereby, even mitochondrial adaptations might be influenced by muscle memory, but it remains to be explored whether repeated endurance training interventions can rely on the same mechanism. Therefore, the overarching aim of the present thesis was to investigate the potential presence of mitochondrial memory in response to repeated high- intensity endurance training interventions. An experimental design composed of two periods of 8 weeks of interval training interspersed by 3 months of detraining was conducted on murine model and humans. In mice, maximal running velocity (Vmax) by graded exercise test (GXT) on a rodent treadmill. In addition, biomarkers of mitochondrial biogenesis and content, and fusion-fission mitochondrial key factors were analyzed on gastrocnemius muscle by western Blot. Results revealed that endurance performance improved to a greater extent after retraining than training. This functional adaptation was supported by a larger mitochondrial content resulting from a more pronounced mitochondrial biogenesis response after retraining. Mitochondrial dynamics were shifted mainly towards fusion, suggesting larger and more elongated mitochondria and finally, the retraining period elicited increased mitophagic flux, which, associated with a smaller increment in the amount of respiratory chain complexes, suggests an improvement in clearance of damaged mitochondria in order to ensure healthier mitochondria and more efficient respiratory function. In humans, maximal aerobic capacity and peak power output were measured and muscle sample from vastus lateralis was used for mitochondrial respiration and epigenetic analysis. Mitochondrial function resulted in a greater improvement after high intensity aerobic stimulus when previous exposure to an identical stimulus has been occurred separated by long-term period of stimulus cessation. The underlying mechanism could reside in epigenetic modifications induced by interval training which led to DNA hypomethylation. Two memory profiles were highlighted at epigenetic level characterized by retention of hypomethylation even during the prolonged detraining period and involving differentially methylated regions related with genes implicated in skeletal muscle metabolic pathways. Overall, these studies provided evidence for a skeletal muscle memory mechanism, specifically at mitochondrial level, elicited by high-intensity aerobic training that affects muscle aerobic phenotype initiating at the epigenetic level and extends upstream to affect mitochondrial function and endurance performance.