Exercise-induced hypertrophic preconditioning alleviates myocardial ischemic injury through trained immunity of macrophages

BACKGROUND: Physical exercise is known to induce trained immunity and improve function of macrophages, and we recently reported that exercise-induced hypertrophic preconditioning (EHP) could protect pathological hypertrophic heart, but it remains unclear whether EHP can mitigate myocardial ischemic injury. Here we hypothesized that EHP would alleviate acute myocardial ischemic injury through trained immunity of macrophages. METHODS: Swimming or treadmill running training was used to induce EHP in C57 mice. After 1-week of exercise termination, mice were subjected to myocardial ischemia/reperfusion (IR). IR injury and inflammatory response and cell energy metabolism reprogramming of bone marrow-derived macrophages (BMDMs) were analysed. Moreover, the effects of exercise on myocardial ischemic injury or long-term survival in patients with acute myocardial infarction (AMI) or history of MI were retrospectively analysed. RESULTS: EHP mice had a significantly smaller infarct size and less apoptotic cardiomyocytes than IR mice without EHP. At 4 weeks after IR, EHP mice had better cardiac function and less myocardial fibrosis. We noted less infiltration and polarization of myocardial M1 macrophages, higher expression of M2 signature anti-inflammatory factors in BMDMs of EHP mice. EHP promoted tricarboxylic acid cycle, mitochondrial oxidative phosphorylation (OXPHOS) and adenosine 5’-monophosphate activated protein kinase (AMPK) phosphorylation, decreased glycolysis and phosphorylation of AKT and mTOR in BMDMs. Importantly, AMPK inhibitor treatment abrogated the cardioprotective effects of EHP, abolishing the improvement in infarct size and apoptosis and reversing the metabolic reprogramming of macrophages. In mice received treadmill running training for 6 weeks, no physiological hypertrophy occurred but myocardial infarct size after IR was significantly reduced. Similarly, in response to AMI, patients with exercise habit had higher left ventricular ejection fraction and lower plasma levels of cardiac troponin T than those sedentary AMI patients. In 2457 patients with self-reported history of MI, patients with regular exercise habit had significantly lower post-MI mortality. CONCLUSIONS: EHP protects heart against myocardial ischemic injury through trained immunity of macrophage mediated by energy metabolism reprogramming.