Abstract
Metabolic cardiomyopathy (MC) is characterized by intracellular lipid accumulation and utilizing fatty acids as a foremost energy source, thereby leading to excess oxidative stress and mitochondrial dysfunction. There is no effective therapy available yet. In this study we investigated whether defective mitophagy contributed to MC and whether urolithin A (UA), a naturally occurring microflora-derived metabolite, could protect against MC in experimental obese mice. Mice were fed high fat diet for 20 weeks to establish a diet-induced obese model. We showed that mitochondrial autophagy or mitophagy was significantly downregulated in the heart of experimental obese mice. UA (50 mg·kg−1·d−1, for 4 weeks) markedly activated mitophagy and ameliorated MC in obese mice by gavage. In PA-challenged H9C2 cardiomyocytes, UA (5 μM) significantly increased autophagosomes and decreased autolysosomes. Furthermore, UA administration rescued PINK1/Parkin-dependent mitophagy and relieved mitochondrial defects in the heart of obese mice, which led to improving cardiac diastolic function and ameliorating cardiac remodelling. In PA-challenged primarily isolated cardiomyocytes, both application of mitophagy inhibitor Mdivi-1 (15 μM) and silencing of mitophagy gene Parkin blunted the myocardial protective effect of UA. In summary, our data suggest that restoration of mitophagy with UA ameliorates symptoms of MC, which highlights a therapeutic potential of UA in the treatment of MC.
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Acknowledgements
This study was supported by grants from the National Natural Science Foundation of China [81573429 to Dr. X Wu; U1601227 to Dr. Yu], and Natural Science Foundation of Guangdong Province [2021A1515012149 to Dr. X Wu].
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XQW and XYY conceived the research. XQW and JRH designed the experiments. JRH, MHZ, YJC, YLS, ZMG, ZJL, GPZ and YQ conducted experiments. XQW and JRH drafted the manuscript. XYY and XYD made critical revision of the manuscript for key intellectual content. All authors discussed the results and commented on the manuscript.
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Huang, Jr., Zhang, Mh., Chen, Yj. et al. Urolithin A ameliorates obesity-induced metabolic cardiomyopathy in mice via mitophagy activation. Acta Pharmacol Sin 44, 321–331 (2023). https://doi.org/10.1038/s41401-022-00919-1
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DOI: https://doi.org/10.1038/s41401-022-00919-1
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