Abstract 19596: Metabolic Remodeling Regulates Cardiac Regeneration in Post-MI Neonatal Mice Heart

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Introduction: The neonatal mouse has a unique regenerative capacity upon myocardial injury during a short time of postnatal development, a capacity that is lost at seven days of age. Previous studies have provided evidence that cardiac regeneration in this model is largely mediated via cardiomyocyte proliferation. We tested the hypothesis whether metabolic remodeling, particularly enhanced glycolysis, could regulate cardiac regeneration and cardiomyocyte proliferation in post-MI neonatal heart.

Methods: 1-day-old (MI P1, n=10) and 7-day-old (MI P7, n=10) mice were exposed to myocardial infarction by LAD ligation. Cardiac function was assessed by echocardiography. Hearts were harvested 21 days after the operation. Volumetric whole-mount 3D imaging was performed by iDISCO and metabolomic profiling by ultra-high performance liquid chromatography-tandem mass spectrometry. Data are presented as mean±SD.

Results: At baseline, P1 mice heart showed enhanced glycolysis and cardiomyocyte proliferation compared to P7 mice. MI P7 mice developed systolic dysfunction (EF 45±9 % vs 62±11 % in MI P1 mice, p≤0.05) and large anterior fibrotic scar (30±18 % vs 3±4 % of LV in MI P1 mice, p≤0.05). MI P1 heart exhibited active regenerative process confirmed as increased cardiomyocyte proliferation (4.4±2.5 % vs. 1.9±2.2 %, p≤0.05). Metabolomic profiling revealed a total of 512 identified metabolites of which 168 metabolites were differentially expressed between M1 P1 and MI P7 groups. Most notably, MI P7 group showed significant decreases in the long-chain and polyunsaturated fatty acids as well as glucose-derived metabolites. Several long-chain acylcarnitines and plasmalogens were also highly elevated in P7 post-MI heart (FC=2.2±1.3, p≤0.05), suggesting mitochondrial dysfunction. In contrast, P1 post-MI hearts showed elevated metabolites related to fructose and glucose metabolism (FC=1.7±0.9, p≤0.05).

Conclusions: The present study supports the notion that the transient regeneration capacity in the neonatal mice heart upon myocardial injury is regulated by metabolic remodeling. Our findings also suggest an important role for glycolysis- and fructolysis-induced cardiomyocyte proliferation in cardiac regeneration.

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