Effects of Exercise Training and TrkB blockade on Cardiac BDNF‐TrkB signaling post Myocardial Infarction in Rats

Abstract

PurposeExercise training post myocardial infarction (MI) is beneficial for preserving cardiac function, but underlying mechanisms are still unclear. Exercise increases brain‐derived neurotrophic factor (BDNF) in the non‐infarct area of the left ventricle (LV) with an improvement of ejection fraction (EF) and LV end‐diastolic pressure (LVEDP). Whether these effects are mediated by downstream pathways of BDNF via its binding receptor tropomyosin‐related kinase B receptor (TrkB) has not yet been assessed. Therefore, impact of exercise training post MI on cardiac function and one of downstream effectors of BDNF‐TrkB signaling, Ca2+/calmodulin dependent protein kinase II (CaMKII), were investigated in exercising rats treated with vehicle or TrkB blocker, ANA‐12.MethodsAfter sham surgery (n=10) or ligation of coronary artery, surviving MI rats were divided into 3 groups: sedentary MI with vehicle (Sed‐MI‐Veh, n=17), exercise MI with vehicle (ExT‐MI‐Veh, n=17) and exercise MI with ANA‐12 (ExT‐MI‐ANA‐12, n=7). Exercise training was done for 4 weeks (5 days/week) on a motor‐driven treadmill with or without ANA‐12 (0.5 mg/kg). At the end, LV function was evaluated by echocardiography and Millar catheter, and mature BDNF (mBDNF), phospho‐CaMKII (p‐CaMKII) and CaMKII (pan) levels were assessed in the non‐infarct area of the LV by Western blotting.ResultsMI size was similar among the MI groups. ExT‐MI‐Veh showed higher EF compared to Sed‐MI‐Veh (63 ± 2 vs. 54 ± 2%, ExT‐MI‐Veh vs. Sed‐MI‐Veh). Exercise‐induced improvement of EF was inhibited by ANA‐12 (56 ± 2%). LVEDP was significantly lower in exercise MI groups (11.6 ± 0.9 and 12.8 ± 1.6 mmHg, Veh and ANA‐12) compared to Sed‐MI‐Veh (18.4 ± 0.9 mmHg). After MI, p‐CaMKII and p‐CaMKII/CaMKII (pan) were significantly decreased (0.6 ± 0.04 and 0.5 ± 0.1, fold of Sham, respectively). Exercise increased mBDNF (0.9 ± 0.1 vs. 0.7 ± 0.1 vs. fold of Sham, ExT‐MI‐Veh vs. Sed‐MI‐Veh) and p‐CaMKII (0.8 ± 0.1, fold of Sham). ANA‐12 prevented exercise‐induced increases in mBDNF (0.6 ± 0.1, fold of Sham) and p‐CaMKII (0.6 ± 0.1, fold of Sham).Conclusions: Exercise post MI increases EF and decreases LVEDP, but TrkB blockade only inhibits the improvement of EF, but not of LVEDP. Exercise increases mBDNF and p‐CaMKII in the non‐infarct area of the LV, which are attenuated by ANA‐12. This indicates that exercise‐induced improvement of EF is mediated by TrkB and downstream effector CaMKII, and BDNF‐TrkB signaling may be mainly associated with improvement in systolic function by exercise training.Support or Funding InformationFRN:MOP‐136923 from the Canadian Institutes of Health Research. Department of Cellular and Molecular Medicine, University of OttawaThis abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.