Molecular Mechanism of Aerobic Exercise Ameliorating Myocardial Mitochondrial Injury in Mice with Heart Failure

To explore the molecular mechanism of aerobic exercise to improve heart failure and to provide a theoretical basis and experimental reference for the treatment of heart failure. Nine-week-old male mice were used to establish a left ventricular pressure overload-induced heart failure model by transverse aortic constriction (TAC). The mice were randomly divided into four groups: a sham group (SHAM), heart failure group (HF), heart failure + SKQ1 group (HS) and heart failure + aerobic exercise group (HE). The mice in the HE group were subjected to moderate-intensity aerobic exercise interventions. The mitochondrion-targeting antioxidant (SKQ1) contains the lipophilic cation TPP, which targets scavenging mitochondrial ROS. The HS group was subjected to SKQ1 (100 nmol/kg/d) interventions, which were initiated 1 week after the surgery, and the interventions lasted 8 weeks. Cardiac function was assessed by ultrasound, cardiomyocyte size by H&E and WGA staining, myocardial fibrosis by Masson’s staining, and myocardial tissue oxidative stress and apoptosis by DHE and TUNEL fluorescence staining, respectively. Western blotting was used to detect the expression of mitochondrial quality control, inflammation, and apoptosis-related proteins. In the cellular level, an in vitro cellular model was established by isolating primary cardiomyocytes from neonatal mice (2–3 days) and intervening with Ang II (1 μM) to mimic heart failure. Oxidative stress and mitochondrial membrane potential were determined in the cardiomyocytes of each group by DHE and JC-1 staining, respectively. Myocardial fibrosis was increased significantly and cardiac function was reduced significantly in the heart failure mice. Aerobic exercise and SKQ1 intervention improved cardiac function and reduced myocardial hypertrophy and myocardial fibrosis in the heart failure mice significantly. Meanwhile, aerobic exercise and SKQ1 intervention reduced the number of DHE-positive particles (p < 0.01) and inhibited myocardial oxidative stress in the heart failure mice significantly. Aerobic exercise also reduced DRP1, Parkin, and BNIP3 protein expression (p < 0.05, p < 0.01), and increased OPA1 and PINK1 protein expression (p < 0.05, p < 0.01) significantly. Moreover, aerobic exercise and SKQ1 intervention decreased the number of TUNEL-positive particles and the expression of inflammation- and apoptosis-related proteins NLRP3, TXNIP, Caspase-1, IL-1β, BAX, BAK, and p53 significantly (p < 0.05, p < 0.01). In addition, the AMPK agonist AICAR and the mitochondria-targeted ROS scavenger (SKQ1) ameliorated AngII-induced mitochondrial fragmentation and decreased mitochondrial membrane potential in cardiomyocytes significantly. It was shown that inhibition of mitochondrial ROS by aerobic exercise, which in turn inhibits mitochondrial damage, improves mitochondrial quality control, and reduces myocardial inflammatory and apoptosis, may be an important molecular mechanism by which aerobic exercise exerts endogenous antioxidant protective effects to improve cardiac function.