Ulk1-mediated Mitophagy in Exercise-induced Adaptations in the Heart and Skeletal Muscle

Regular exercise reduces all-cause mortality and is the most effective intervention for prevention and treatment of many diseases, including diabetes mellitus. Though exercise has been widely implemented and practiced since ancient times, the molecular mechanism(s) behind its benefits are still largely elusive. An example is the exercise-mediated protection in diabetes mellitus patients. Millions of diabetic patients suffer from cardiovascular complications, while an important early sign of which is diastolic dysfunction. Clinical studies have proven that regular exercise is highly effective in preventing and treating diastolic dysfunction in diabetes, but the underlying mechanism(s) remain poorly understood. Here, this thesis presents a series of studies aiming to: 1) Establish a mouse model of exercise-mediated protection in the diabetic heart to study its mechanism(s), 2) Investigate the necessisty of ULK1 activation by phosphorylation of serine 555 in exercise-mediated protection in the diabetic heart, and 3) Investigate the necessisty of ULK1 phosphorylation of serine 555 in skeletal muscle and metabolic adaptations to exercise in healthy, non-diabetic mice.
We found that in the diabetic heart, exercise intervention managed to mitigate exercise intolerance, diastolic dysfunction, compromised mitochondrial quality and elevated oxidative stress caused by diabetes. Phosphorylation of ULK1 at S555 seemed to be important in acute exercise-induced mitophagy in the heart, but not required for the functional protection in diabetes. Similarly, in healthy mice, although loss of ULK1 phosphorylation at S555 caused a mild metabolic impairment during exercise, the benefits conferred by exercise training are largely retained. Therefore, we concluded that the exercise-mediated protection in the diabetic heart as well as the exercise benefits in healthy mice are independent of ULK1 phosphorylation at S555. Overall, these studies provide important mechanistic insights into the understanding of the molecular pathways that are involved in exercise-mediated benefits, and laid a solid foundation for future research in molecular exercise sciences.