# PKM1 is required for embryonic cardiomyocyte proliferation through energetic regulation of NFYa stability

## TL;DR

This study shows that PKM1 is essential for heart development in embryos by regulating energy metabolism and cell proliferation.

## Contribution

A new Pkm1 mutant mouse model was developed to study PKM1's role without compensation from PKM2.

## Key findings

- PKM1 maintains ATP levels to inhibit AMPK and stabilize NFYa, promoting cardiomyocyte proliferation.
- Loss of PKM1 leads to cardiac dysfunction and reduced cardiomyocyte proliferation in embryos.
- The PKM1-AMPK-NFYa axis links energy metabolism to heart development and cell cycle regulation.

## Abstract

Pyruvate kinase M1 (PKM1) is a critical enzyme in glycolysis, particularly in high-energy-demand tissues like the heart. However, previous knockout strategies for PKM1 were confounded by compensatory upregulation of its low-activity splice variant, PKM2. Here, we generated a Pkm1 mutant mouse model using a point mutation that eliminates PKM1 without compensatory PKM2 upregulation. Homozygous Pkm1 mutants exhibited perinatal lethality associated with cardiac dysfunction, characterized by thin myocardium and reduced cardiomyocyte proliferation during mid-to-late gestation. We found that PKM1 sustains ATP levels to inhibit AMPK, which otherwise promotes NFYa phosphorylation and destabilization. NFYa, a transcription factor essential for cardiomyocyte proliferation, has been identified as a key mediator linking metabolic status to cell cycle. These findings identify the PKM1-AMPK-NFYa axis in energetic regulation of cardiomyocyte proliferation in the embryonic heart, offering new insights into the function of PKM1 and the broader impact of energy metabolism on cardiac development, while also shedding light on the potential metabolic underpinnings of congenital heart diseases.