Role of FOXO Transcription Factors in the Protective Mechanism by Resveratrol Against Cardiomyopathy in the Dystrophin-deficient Mdx Mouse

Abstract

Purpose: FOXO transcription factors (FOXO) transcriptionally regulate anti-oxidant and autophagy-related genes and elicit cellular stress resistance. We previously reported that treatment with resveratrol (RSV), an activator of the deacetylase SIRT1, ameliorates cardiomyopathy in the dystrophin-deficient mdx mouse (MDX), a model of Duchenne muscular dystrophy. Since SIRT1 is known to activate FOXO under stress conditions, we hypothesized that FOXO play roles in protection by RSV in the mdx heart. Methods and Results: In Experiment 1, we analyzed cardiac phenotypes in MDX. At 42-week-old, MDX showed cardiac hypertrophy evaluated by heart weight and echocardiography compared with age-matched C57BL10 mice. Left ventricular (LV) systolic function was preserved in MDX at this age. Dihydroethidium (DHE) staining for analysis of cardiac superoxide anion showed that fluorescence intensity was 4.5-fold higher in MDX than control C57BL10. Immunoblot showed that myocardial p62 and LC3-II levels were increased in MDX at 24-week-old, and this was associated with increased phosphor-S6 level, suggesting impaired autophagy due to mTORC1 activation. In Experiment 2, MDX were divided into untreated (RSV0) and RSV-treated (400 mg/kg chow, RSV400) groups. RSV administration was started at 8-week-old, and mice were sacrificed at 65-week-old. Echocardiography at 62-week-old demonstrated that LV fractional shortening was higher (38±2% vs. 34±1%, P Conclusions: RSV ameliorated cardiomyopathy in the mdx mouse probably by attenuating oxidative stress and restoring autophagy via FOXO3a activation.