Fasting increases susceptibility to acute myocardial ischaemia/reperfusion injury through a sirtuin-3 mediated increase in fatty acid oxidation

Fasting increases susceptibility to acute myocardial ischaemia/reperfusion injury (IRI) but the mechanisms are unknown. Here, we investigate the role of the mitochondrial NAD + -dependent deacetylase, Sirtuin-3 (SIRT3), which has been shown to influence fatty acid oxidation and cardiac outcomes, as...

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Bibliographic Details
Published in:Scientific reports 2022-11, Vol.12 (1), p.20551-20551, Article 20551
Main Authors: Hall, Andrew R., Karwi, Qutuba G., Kumar, Sanjeev, Dongworth, Rachel, Aksentijević, Dunja, Altamimi, Tariq R., Fridianto, Kevin Timothy, Chinda, Kroekkiat, Hernandez-Resendiz, Sauri, Mahmood, Mohammad U., Michelakis, Evangelos, Ramachandra, Chrishan J., Ching, Jianhong, Vicencio, Jose M., Shattock, Michael J., Kovalik, Jean-Paul, Yellon, Derek M., Lopaschuk, Gary, Hausenloy, Derek J.
Format: Article
Language:English
Subjects:
631/443/592
631/443/592/75
631/443/592/75/2
631/443/592/75/2/1674
Animals
Fasting
Fatty Acids
Glucose
Glucose metabolism
Heart
Humanities and Social Sciences
Ischemia
Metabolism
Mice
Mice, Knockout
Mitochondria
multidisciplinary
Myocardial infarction
Myocardial Reperfusion Injury - genetics
Oxidation
Reperfusion
Science
Science (multidisciplinary)
Sirtuin 3 - genetics
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Summary:Fasting increases susceptibility to acute myocardial ischaemia/reperfusion injury (IRI) but the mechanisms are unknown. Here, we investigate the role of the mitochondrial NAD + -dependent deacetylase, Sirtuin-3 (SIRT3), which has been shown to influence fatty acid oxidation and cardiac outcomes, as a potential mediator of this effect. Fasting was shown to shift metabolism from glucose towards fatty acid oxidation. This change in metabolic fuel substrate utilisation increased myocardial infarct size in wild-type (WT), but not SIRT3 heterozygous knock-out (KO) mice. Further analysis revealed SIRT3 KO mice were better adapted to starvation through an improved cardiac efficiency, thus protecting them from acute myocardial IRI. Mitochondria from SIRT3 KO mice were hyperacetylated compared to WT mice which may regulate key metabolic processes controlling glucose and fatty acid utilisation in the heart. Fasting and the associated metabolic switch to fatty acid respiration worsens outcomes in WT hearts, whilst hearts from SIRT3 KO mice are better adapted to oxidising fatty acids, thereby protecting them from acute myocardial IRI.
ISSN:2045-2322
2045-2322
DOI:10.1038/s41598-022-23847-w