Mithochondrial function in human skeletal muscle : with special reference to exercise and training

Sammanfattning: The overall objective of this thesis was to study the adaptation of oxidative function in human skeletal muscle to acute exercise of different modes, intensities and durations, and to endurance training. The effects of endurance training on mitochondrial function were evaluated in cross-sectional and longitudinal studies by measurements of mitochondrial oxygen consumption in isolated mitochondria and permeabilised muscle fibres and measurements of mitochondrial ATP production rate in isolated mitochondria. A positive correlation was observed between maximal mitochondrial oxidative power measured in isolated mitochondria and permeabilised muscle fibres and other parameters related to local and whole body aerobic training status such as pulmonary maximal oxygen uptake, lactate threshold, and muscle activity of citrate synthase (CS). Previous studies have demonstrated that ADP and creatine are important regulators of oxidative phosphorylation. We found that the sensitivity of oxidative phosphorylation to ADP at the level of individual mitochondrion exhibits negative correlation with training status, whereas the creatine control of mitochondrial respiration is more pronounced in aerobically well-trained individuals. It is suggested that these adaptations may improve the potential for regulation of oxidative metabolism in trained muscle. The sensitivity of proton leakdependent oxygen consumption in isolated mitochondria to free fatty acids was up-regulated by a short-term endurance-training program. This may contribute to a higher basal metabolic rate in endurance-trained individuals. It is also suggested that this adaptation may prevent excessive free radical generation and enhance the potential for regulation of aerobic energy production in trained muscle. Exposure of isolated mitochondria to reactive oxygen species (ROS) reduced maximal ADP-stimulated respiration and P/O ratio and increased noncoupled respiration rate. The sensitivity of non-coupled respiration in isolated mitochondria to ROS was increased by 6 wk of endurance training, whereas the sensitivity of maximal ADP-stimulated respiration and P/O ratio to ROS was unaffected. These results indicate that inner mitochondrial membrane becomes more sensitive to oxidative stress after short-term endurance training. Activities of muscle antioxidative enzymes (SOD, GPX) and glutathione status were unaffected by training. This will result in a lowered antioxidative protection per mitochondrion, which may increase the susceptibility of inner membrane to oxidative stress. Maximal mitochondrial oxidative power in human vastus lateralis muscle was found to be intact or improved after high-intensity intermittent and moderate-intensity prolonged concentric cycling exercise as well as after eccentric cycling. Prolonged exercise increased the non-coupled mitochondrial respiration rate, which may contribute to the excess post-exercise oxygen consumption. After prolonged exercise an acute increase in muscle CS activity was observed. High-intensity intermittent exercise affected the ADP control of oxidative phosphorylation, as evidenced by transient decrease in ADP sensitivity of mitochondrial respiration in permeabilised muscle fibres. ADP sensitivity was unchanged after prolonged concentric and high-intensity eccentric exercise. Taken together these results indicate that mitochondrial function in human muscle is affected differently by exercise of different types. The effect of lactic acidosis on oxidative phosphorylation was evaluated in isolated mitochondria from rat skeletal muscle. It was demonstrated that acidosis induced on non-phosphorylating mitochondria reduces rate of subsequent maximal ADP-stimulated respiration. In contrast, when actively phosphorylating mitochondria were exposed to acidosis maximal ADP-stimulated respiration remained unchanged. On the basis of these results we suggested that the influence of lactic acidosis on muscle aerobic energy production may depend on the physiological conditions at the onset of acidity. Overall, the present investigations indicate that mitochondrial oxidative function is highly responsive to exercise. Endurance training induces adaptation of both quantitative and qualitative aspects of mitochondrial function, which improves the potential for metabolic control. The results suggest that acute physical exercise in humans is, in contrast to previous animal studies, well tolerated by skeletal muscle mitochondria.