Effects of exercise training and TrkB blockade on cardiac function and BDNF-TrkB signaling postmyocardial infarction in rats

Exercise training is beneficial for preserving cardiac function post myocardial infarction (MI), but the underlying mechanisms are not well understood. We investigated one possible mechanism, brain-derived neurotrophic factor (BDNF)-tropomyosin-related kinase B (TrkB) signaling with the TrkB blocker, ANA-12 (0.5 mg/kg/day). Male Wistar rats underwent sham surgery or ligation of left descending coronary artery. Surviving MI rats were allocated to sedentary MI with vehicle (Sed-MI-Veh), exercise MI with vehicle (ExT-MI-Veh) and exercise MI with ANA-12 (ExT-MI-ANA-12). Exercise training was done 5 days/week for 4 weeks on a motor-driven treadmill. At the end, LV function was evaluated by echocardiography and Millar catheter. Mature BDNF (mBDNF) and downstream effectors of BDNF-TrkB signaling, Ca2+/calmodulin dependent protein kinase II (CaMKII), Akt and adenosine monophosphate-activated protein kinase (AMPK), were assessed in the non-infarct area of the LV by Western blotting. Exercise training increased stroke volume (SV) and cardiac index, and attenuated the decrease in ejection fraction (EF) and the increase in LV end-diastolic pressure (LVEDP) post MI. ANA-12 blocked the improvement of EF and attenuated the increases in SV and cardiac index, but did not affect LVEDP. Exercise training post MI prevented decreases in mBDNF, phosphorylated CaMKII (p-CaMKII), p-Akt and p-AMPKα expression. These effects were all blocked by ANA-12 except for p-AMPKα. In conclusion, exercise-induced improvement of EF is mediated by the BDNF-TrkB axis and downstream effectors CaMKII and Akt. BDNF-TrkB signaling appears to contribute to the improvement in systolic function by exercise training.