Role of autophagy-mediated clearance of mitochondria in cardioprotection afforded by the protein deacetylase SIRT1 in dystrophin-deficient mdx mice Atsushi Kuno, Ryusuke Hosoda, Hiromi Sakuragi, Yoshiyuki Horio Department of Pharmacology, Sapporo Medical University School of Medicine, Japan
Heart failure is the main cause of death in patients with Duchenne muscular dystrophy. The role of mitochondrial autophagy in dystrophic cardiomyopathy is unknown. SIRT1, an NAD+-dependent deacetylase, promotes autophagy for cellular adaptation in response to various stresses. Here, we hypothesized that activation of SIRT1 ameliorates dystrophic cardiomyopathy by facilitating mitochondrial autophagy. In the dystrophin-deficient mdx mouse at 22-week-old (wo), immunoblot revealed that cardiac levels of LC3-II, an autophagosome marker, and p62, which is degraded by autophagy, were significantly higher than those in age-matched control mice, suggesting autophagosome accumulation via disturbed lysosomal degradation. Immunostaining showed that LC3 dot level and co-localization of fragmented mitochondria within LC3 dots were significantly increased in the mdx heart, suggesting impaired autophagy-mediated elimination of damaged mitochondria. Copy number of mitochondrial DNA (mtDNA) relative to nuclear DNA was unchanged in mdx. However, long range PCR revealed that mtDNA with deletion was markedly increased in mdx hearts, supporting the notion that damaged mitochondria is accumulated in the mdx heart. Dihydroethidium (DHE) staining, that detects superoxide, was also higher in the mdx heart. Next, mdx mice treated with the SIRT1 activator resveratrol (RSV, 50 mg/kg/day) starting at the 9-wo and untreated mdx mice were compared. Echocardiography at 62-wo showed higher %FS and smaller left ventricular dimensions in RSV-treated mice. RSV reduced LC3 level in immunoblot and co-localization of LC3 dot and Rieske in immunostaining, suggesting promotion of autophagy-mediated degradation of mitochondria. Consistent with these findings, levels of mtDNA with deletion and DHE staining were reduced and mitophagy-related genes were upregulated by RSV in mdx heart. In conclusion, these findings suggest that activation of SIRT1 facilitates autophagy-mediated elimination of damaged mitochondrial, which may results in attenuation of oxidative stress and improves dystrophic cardiomyopathy.
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