Abstract 19320: Intensity-dependent Exercise Regulates Mitochondrial Quality Control to Attenuate Cardiac Remodeling in Aged Mice

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Background: Exercise protects against myocardial infarction (MI). However, the relationship between favorable cardioprotections and the intensity of exercise for the elderly patients remains controversy.

Methods and Results: 18-months-old male mice were subjected to MI. Four months later, mice were randomly subjected to different intensity of exercises, including 15 min’s and 60 min’s swimming training (ST) once per day, five times a week for 8 weeks. Compared to Vehicle, 15 min’s ST significantly increased survival rate post-MI (P<0.05), augmented left ventricle ejection fraction (1.5-fold, P<0.01) and decreased heart size. It also suppressed myocardial interstitial fibrosis (P<0.01) and apoptosis (56.1%, P<0.01). However, 60 min’s ST did not present significant cardioprotective effects. When measuring mitochondrial quality control, 15 min’s ST improved the mitochondrial morphology and the respiration function (P<0.01). Meanwhile, 15 min’s ST decreased the level of fusion proteins Mfn1, Mfn2 and fission protein Drp1 (48.3%, 28.7% and 64.3% reduction, P<0.01, respectively) while increased Opa1 expression for 31.8% (P<0.01). Moreover, 15 min’s ST dramatically declined the level of LC3II (73.7%, P<0.01) together with an inhibition of P62 (39.3%, P<0.05), aiding the autophagic flux. Conversely, 60 min’s ST reduced LC3II expression (35.0%, P<0.01) but increased the level of P62 (40.1%, P<0.05). Furthermore, 15 min’s ST enhanced ROS scavenging determined by SOD2 activity (P<0.01) and DHE staining (P<0.05). Notably, 15 min’s ST significantly increased Sirtuin (SIRT) 3 level (3.3-fold, P<0.01) while treating senescent H9C2 cells with lentivirus to knockdown SIRT3 seen that inhibition of SIRT3 increased cell LDH release (P<0.01) and ROS production (P<0.01) under hypoxia injury. In addition, inhibition of SIRT3 augmented mitochondrial fission protein Drp1 expression (P<0.05) and regulated mitophagy with a significant LC3II accumulation and a rise of P62 (P<0.05, respectively) in senescent cardiomyocytes.

Conclusion: Collectively, our study demonstrated for the first time that intensity-dependent exercise attenuated post-MI remodeling via SIRT3-dependent regulation of mitochondrial quality control in aged Mice.

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