Abstract
Autophagy activation improves the phenotype in mdx mice, a Duchenne muscular dystrophy (DMD) model, although the underlying mechanisms are obscure. We previously found that resveratrol, a strong inducer of autophagy, ameliorates the cardiac pathology of mdx mice. Autophagy could eliminate damaged mitochondria, a major source of intracellular reactive oxygen species (ROS), although there is no evidence for mitochondriopathy in dystrophic cardiomyopathy. To elucidate resveratrol’s function, we investigated the deletion of mitochondrial DNA (mtDNA), autophagy of damaged mitochondria (mitophagy), and ROS accumulation in the mdx mouse heart. Low levels of normal mtDNA and abnormal accumulations of mitochondria-containing autophagosomes were found in the mdx mouse heart. Administering resveratrol to mdx mice for 56 weeks ameliorated the cardiomyopathy, with significant reductions in the amount of mtDNA deletion, the number of mitochondria-containing autophagosomes, and the ROS levels. Resveratrol induced nuclear FoxO3a accumulation and the expression of autophagy-related genes, which are targets of FoxOs. The most effective dose in mdx mice was 0.4 g resveratrol/kg food. In conclusion, resveratrol improved cardiomyopathy by promoting mitophagy in the mdx mouse heart. We propose that acquired mitochondriopathy worsens the pathology of DMD and is a potential therapeutic target for the cardiomyopathy in DMD patients.
Highlights
Autophagy is a cell system for discarding damaged proteins and disabled organelles including mitochondria by sequestrating them into a double-membraned autophagosome, which fuses with a lysosome to digest the autophagosomal contents[8]
We previously reported that expression levels of nicotinamide adenine dinucleotide phosphate (NADPH) oxidase 4 (NOX4), which generates superoxide anion, were upregulated in the skeletal muscle from mdx mice[16]
We found that resveratrol significantly upregulated autophagy-related genes, including Map1lc3B, Bnip[3], Becn[113], Rab[723], Pink[113], Sqstm[124], and Ctsl[25], which are transactivated by FoxOs (Fig. 5A)
Summary
Autophagy is a cell system for discarding damaged proteins and disabled organelles including mitochondria by sequestrating them into a double-membraned autophagosome, which fuses with a lysosome to digest the autophagosomal contents[8]. Autophagy is reported to be impaired in muscular dystrophies, and the activation of autophagy by low-amino-acid intake ameliorates the skeletal muscle phenotype of mouse models of muscular dystrophies including dystrophin-deficient mdx mice, a model of DMD9,10. It remains unknown whether an alteration in mitochondria autophagy (mitophagy) contributes to the pathology of DMD. We previously showed that treatment with resveratrol, a SIRT1 activator, significantly reduces the muscle ROS levels[16] and improves the cardiomyopathy in mdx mice[17]. We further examined whether resveratrol administration promotes mitophagy, reduces ROS levels, and ameliorates the cardiac pathophysiology in the mdx mice
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
