Pkm1 is required for embryonic cardiomyocyte proliferation through energetic regulation of NFYa stability
Pyruvate Kinase M1 (PKM1) is a critical enzyme in energy metabolism, 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 deletes Pkm1 without elevating PKM2. 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, is identified as a key mediator linking metabolic status to cell cycle activity. These findings identify the PKM1-AMPK-NFYa axis in energetic regulation of cardiomyocyte proliferation in 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. Overall design: RNA-seq profiling of wildtype and pkm1-knockout mouse hearts at embryonic days 18.5.