Role of phosphofructokinase in myocardial regeneration
Description: Heart disease is the leading cause of death and illness in the United States, with a major challenge being the inability of adult hearts to regenerate tissue after injuries such as heart attacks. Interestingly, certain non-mammalian vertebrates like zebrafish, and even neonatal mice for a brief period after birth, can fully regenerate their hearts after injury. This ability is linked to their lower mitochondrial content, which leads to a metabolic shift from glycolysis in embryonic and neonatal cardiomyocytes to oxidative phosphorylation in adult cardiomyocytes. This metabolic shift induces DNA damage and contributes to postnatal cell-cycle exit, highlighting the central role of cardiac metabolism in regeneration. Stimulating glucose metabolism could promote heart regeneration by mimicking the metabolic profile of a regenerative neonatal heart. Understanding how to modulate this switch could uncover new therapeutic strategies for heart disease. We recently found that the phosphofructokinase-2 (PFK-2) inhibitor 3PO injection in neonatal mice inhibits cardiomyocyte proliferation and heart regeneration following myocardial infarction (MI). Our results indicate that PFK-2 is essential for cardiac regeneration post-MI. However, the mechanisms by which cardiac-specific PFK-2 overexpression prologs the postnatal window of cardiomyocyte proliferation and reduces infarction size remain unclear. We hypothesize that targeting PFK-2, a key regulator of glucose metabolism, could promote heart regeneration after injury through enhanced glucose metabolism. To test this, we propose two aims: 1) to investigate whether cardiac-specific PFK-2 overexpression can extend the postnatal cardiomyocyte proliferation window and promote heart myocardial regeneration following injury, and 2) to determine the metabolic and molecular mechanisms by which cardiac-specific PFK-2 overexpression promotes post-MI regeneration in mammalian hearts. We will use genetic mouse models to specifically increase cardiac glucose metabolism through PFK-2 overexpression (GlycoHi mice). The outcome of this study will provide mechanistic insights into heart regeneration following MI and contribute to developing strategies to prevent heart failure. In line with the AHA Institutional Research Enhancement Award (AIREA) program, this study will also support the training and education of talented undergraduate and graduate students from diverse backgrounds in heart failure and regeneration research.
Funder: American Heart Association
Amount: $200,000
Funding type: research
Funder scheme: AHA Institutional Research Enhancement Award
Start date: 2025-01-01
End date: 2026-12-31
Investigators: Jiyoung Bae, Jiyoung Bae
Institution: Oklahoma State University
Subfield: Molecular Biology
Domain: Life Sciences
Funded outputs count: 1
Funder award ID: 25AIREA1377296
OpenAlex ID: G4968153754