Malonate Promotes Adult Cardiomyocyte Proliferation and Heart Regeneration

Neonatal mouse cardiomyocytes undergo a metabolic switch from glycolysis to oxidative phosphorylation, which results in a significant increase in reactive oxygen species production that induces DNA damage. These cellular changes contribute to cardiomyocyte cell cycle exit and loss of the capacity fo...

Full description

Saved in:
Bibliographic Details
Published in:Circulation (New York, N.Y.) N.Y.), 2021-05, Vol.143 (20), p.1973-1986
Main Authors: Bae, Jiyoung, Salamon, Rebecca J, Brandt, Emma B, Paltzer, Wyatt G, Zhang, Ziheng, Britt, Emily C, Hacker, Timothy A, Fan, Jing, Mahmoud, Ahmed I
Format: Article
Language:English
Subjects:
Animals
Cardiovascular Diseases - drug therapy
Cell Proliferation
Humans
Male
Malonates - pharmacology
Malonates - therapeutic use
Mice
Myocardium - pathology
Myocytes, Cardiac - drug effects
Regeneration - drug effects
Signal Transduction
Citations: Items that this one cites
Items that cite this one
Online Access:Get full text
Tags: Add Tag
No Tags, Be the first to tag this record!
Description
Summary:Neonatal mouse cardiomyocytes undergo a metabolic switch from glycolysis to oxidative phosphorylation, which results in a significant increase in reactive oxygen species production that induces DNA damage. These cellular changes contribute to cardiomyocyte cell cycle exit and loss of the capacity for cardiac regeneration. The mechanisms that regulate this metabolic switch and the increase in reactive oxygen species production have been relatively unexplored. Current evidence suggests that elevated reactive oxygen species production in ischemic tissues occurs as a result of accumulation of the mitochondrial metabolite succinate during ischemia via succinate dehydrogenase (SDH), and this succinate is rapidly oxidized at reperfusion. Mutations in SDH in familial cancer syndromes have been demonstrated to promote a metabolic shift into glycolytic metabolism, suggesting a potential role for SDH in regulating cellular metabolism. Whether succinate and SDH regulate cardiomyocyte cell cycle activity and the cardiac metabolic state remains unclear. Here, we investigated the role of succinate and SDH inhibition in regulation of postnatal cardiomyocyte cell cycle activity and heart regeneration. Our results demonstrate that injection of succinate into neonatal mice results in inhibition of cardiomyocyte proliferation and regeneration. Our evidence also shows that inhibition of SDH by malonate treatment after birth extends the window of cardiomyocyte proliferation and regeneration in juvenile mice. Remarkably, extending malonate treatment to the adult mouse heart after myocardial infarction injury results in a robust regenerative response within 4 weeks after injury via promoting adult cardiomyocyte proliferation and revascularization. Our metabolite analysis after SDH inhibition by malonate induces dynamic changes in adult cardiac metabolism. Inhibition of SDH by malonate promotes adult cardiomyocyte proliferation, revascularization, and heart regeneration via metabolic reprogramming. These findings support a potentially important new therapeutic approach for human heart failure.
ISSN:0009-7322
1524-4539
DOI:10.1161/CIRCULATIONAHA.120.049952