Excessive exercise training causes mitochondrial functional impairment and decreases glucose tolerance in healthy volunteers

Exercise training positively affects metabolic health through increased mitochondrial oxidative capacity and improved glucose regulation and is the first line of treatment in several metabolic diseases. However, the upper limit of the amount of exercise associated with beneficial therapeutic effects has not been clearly identified. Here, we used a training model with a progressively increasing exercise load during an intervention over 4 weeks. We closely followed changes in glucose tolerance, mitochondrial function and dynamics, physical exercise capacity, and whole-body metabolism. Following the week with the highest exercise load, we found a striking reduction in intrinsic mitochondrial function that coincided with a disturbance in glucose tolerance and insulin secretion. We also assessed continuous blood glucose profiles in world-class endurance athletes and found that they had impaired glucose control compared with a matched control group. [Display omitted] •Here, we investigate the dose-response effects of exercise training in healthy subjects•Excessive exercise training induces substantial mitochondrial respiratory impairment•Mitochondrial impairment is associated with impaired glucose tolerance•Despite excessive training, markers of global oxidative stress were unchanged Flockhart and colleagues investigated the dose-response relationship of exercise training and found that excessive training causes mitochondrial impairment and reduced glucose tolerance in healthy volunteers. Mitochondrial ROS production was reduced, thereby maintaining total oxidative stress. In a separate cohort, disturbed glucose control was found in free-living elite endurance athletes.