Background <p>Exercise is an important method of promoting health. But unscientific high-intensity exercise is harmful to health. Extreme high-intensity exercise could lead to serious cardiac events such as sudden cardiac death. However, myocardial injury and the metabolic changes have been little studied. Our study aimed to explore the changes in myocardial tissue and metabolism after high-intensity exercise, while investigating the relationship between key metabolites and diseases that cause myocardial injury in population.</p> Methods <p>We investigated myocardial injury through serum myocardial injury markers and myocardial pathology in mice after single exhaustion swimming. Machine learning combined with metabolomics were used to study myocardial metabolic changes and select key metabolites. Mendelian randomization was utilized to test the applicability of the results of animal experiments in the population.</p> Results <p>Our study found that high-intensity exercise resulted in significant elevation of serum markers of myocardial injury, significant pathological changes in the myocardium, and significant alterations in myocardial metabolism. Mendelian randomization revealed that decreased expression of the key metabolite asparagine might associate with chronic ischemic heart disease, consistent with the results of animal experiments.</p> Conclusions <p>This study found that high-intensity exercise could cause myocardial injury and significantly affect myocardial metabolic profiles. The selected key metabolite asparagine was a protective factor against chronic ischemic heart disease in population. Our study provides new insights into high-intensity exercise-associated myocardial injury and new strategies for human health protection.</p> Graphical abstract <p></p>