Aerobic Exercise Improves Cardiac Function in Myocardial Infarction Mice by Suppressing Sympathetic Overactivation through “Brain-Heart” Axis

Objective: To explore the central mechanism of aerobic exercise in improving cardiac function in mice with myocardial infarction（MI）. Methods: C57BL/6J mice were randomly divided into Sham group, MI group and MI exercise group, with 12 mice in each group; photogenetic activation group（ChR2）, photogenetic inhibition group（eNpHR3.0）, with 6 mice in each group;myocardial infarction control group（MI+Dio）, myocardial infarction+M1 neuronal ablation group（MI+taCasp3）, with 6 mice in each group. The MI model was prepared by ligation of the anterior descending branch in the left coronary artery. In the ME group, 6-wk aerobic exercise training was performed at 1-wk after operation. Retrograde transsynaptic labeling was performed by cardiac injection of pseudorabies virus. The effect of M1 Glu neurons on cardiac sympathetic nerve was investigated by photogenetic activation or inhibition of M1 Glu neurons and neuronal ablation technique to silence M1 Glu neurons. The pathological changes of cardiac structure were evaluated by Masson and HE staining. ECG was used to detect heart rate variability. Cardiac function was assessed by echocardiography, and serum NE content was detected by the ELISA kit. The expressions of TH, GAP43 and NGF in cardiac, as well as c-Casps3, TNF-α and IL-6 in the M1 region were detected by Western blotting and immunofluorescence. Nissl staining and MAP-2 immunofluorescence staining was used to assess neuronal damage. The ultrastructure of neurons in M1 region was observed by electron microscope. Results: A large number of labeled neurons were observed in L5 layer of M1 region after 5.5days of PRV injection in left ventricular. Photogenetic activation or inhibition of M1 Glu neurons significantly increased or decreased the LF/HF power ratio. Compared with MI+Dio group, the serum NE content, LF/HF power ratio, TH, GAP43 and NGF expression in MI+taCsap3 group were significantly decreased. Compared with Sham group, MI group showed decreased MAP-2expression and Nissl body density, the mitochondrial swelling, division, crista lysis and other ultrastructural pathological were changed, and the c-Caspase3, TNF-α and IL-6 expression were increased. However, aerobic exercise intervention significantly reversed the change. Compared with Sham group, the power ratio of LF/HF in MI group was significantly increased, the distribution area and density of myocardial NGF and TH and myocardial collagen fibers were significantly increased, and the cardiac function was decreased, which was significantly reversed after aerobic exercise intervention. Conclusions: Due to the projection link between the neuronal chain governing cardiac activity and M1 Glu neurons, the inhibitionof M1 Glu neuron activity can improve the overactivation of sympathetic nerve and the malignant remodeling of the heart after myocardial infarction. Aerobic exercise can alleviate the damage of M1 neurons, inhibit the malignant remodeling of cardiac sympathetic nerve and improve cardiac function after myocardial infarction. It is suggested that the research focus on the neuroregulation and cardiac protection in the M1 region of the primary motor cortex of the brain may provide new ideas for non-invasive treatment or prevention of myocardial ischemic injury in the future.