From THE DEPARTMENT OF PHYSIOLOGY AND PHARMACOLOGY Karolinska Institutet, Stockholm, Sweden EXERCISE STRATEGIES TO IMPROVE AEROBIC CAPACITY, INSULIN SENSITIVITY AND MITOCHONDRIAL BIOGENESIS

Regular exercise plays a key role in the maintenance of health and physical capabilities. Extensive research shows that exercise is an efficient method to prevent diabetes. Both resistance and aerobic exercise training are well known countermeasures for insulin resistance. However, depending on factors like purpose, capability and accessibility, different exercise modes need to be evaluated on both applied and molecular levels. In addition, exercise is the means to improve performance. New training strategies have emerged, like training with low glycogen stores or combining strength with endurance training, and guidelines based on empirical data are needed. Although knowledge of exercise physiology has advanced, much more needs to be learned before we can exploit the full potential of exercise with regard to health and performance. Therefore, the overall aim of this thesis is to provide knowledge of how different exercise strategies improve performance and insulin sensitivity. The mitochondria represent a central part of this thesis considering their key role in both health and performance. Study I was an acute crossover investigation of the effect of exercise with low glycogen levels on markers of mitochondrial biogenesis. Study II investigated the effect of concurrent resistance and endurance training on mitochondrial density and endurance performance. Study III investigated the acute effect of exercise on starvation-induced insulin resistance. In Study IV, the effect of resistance exercise training on health and performance in the elderly was investigated. The main findings were:  Training with low glycogen levels enhanced the response in markers of mitochondrial biogenesis.  Adding resistance training to endurance training did not improve mitochondrial density or endurance performance in trained individuals.  Resistance training for only eight weeks is an efficient strategy to improve strength, heart rate (HR) during submaximal cycling and glucose tolerance in elderly. It also improves muscular quality by increasing mitochondrial and hypertrophy signaling proteins.  Starvation-induced insulin resistance is attenuated by exercise. Mitochondrial respiration and reactive oxygen species (ROS) production is reduced during starvation. Exercise during starvation reduced glycogen stores and resulted in the activation of enzymes involved in glucose metabolism.  When exercise was performed during starvation there was an increase in markers for mitochondrial lipid oxidation. In conclusion, training with low glycogen stores seems to be a promising strategy to increase mitochondrial density. In contrast to our previous acute findings, concurrent training had no effect on mitochondrial biogenesis or endurance performance. Exercise can reverse yet another mode of insulin resistance (starvation) which strengthens its role in the treatment for other states of insulin resistance, e.g. Type 2 diabetes (T2D). Resistance exercise training is an efficient and safe strategy for the elderly to improve health and performance. LIST OF SCIENTIFIC PAPERS I. Niklas Psilander, Per Frank, Mikael Flockhart, and Kent Sahlin. Exercise with low glycogen increases PGC-1a gene expression in human skeletal muscle. Eur J Appl Physiol 113:951–963, 2013. II. Niklas Psilander, Per Frank, Mikael Flockhart, and Kent Sahlin. Adding strength to endurance training does not enhance aerobic capacity in cyclists. SJMSS, accepted. III. Per Frank, Abram Katz, Eva Andersson, and Kent Sahlin. Acute exercise reverses starvation-mediated insulin resistance in humans. Am J Physiol Endocrinol Metab 304: E436–E443, 2013. IV. Per Frank, Eva Andersson, Marjan Pontén, Björn Ekblom, Maria Ekblom, and Kent Sahlin. Resistance training improves aerobic capacity and glucose tolerance in elderly. Submitted. CONTENTS