Abstract
Adult mammalian cardiomyocytes (CM) are postmitotic, differentiated cells that cannot re-enter the cell cycle after any appreciable injury. Therefore, understanding the factors required to induce CM proliferation for repair is of great clinical importance. While expression of muscle pyruvate kinase 2 (Pkm2), a cytosolic enzyme catalyzing the final step in glycolysis, is high in end-stage heart failure (HF), the loss of Pkm2 promotes proliferation in some cellular systems, in vivo. We hypothesized that in the adult heart CM proliferation may require low Pkm2 activity. Thus, we investigated the potential for Pkm2 to regulate CM proliferation in a mouse model of myocardial infarction (MI) employing inducible, cardiac-specific Pkm2 gene knockout (Pkm2KOi) mice. We found a lack of cardiac hypertrophy or expression of the fetal gene program in Pkm2KOi mice post MI, as compared to vehicle control animals (P < 0.01), correlating with smaller infarct size, improved mitochondrial (mt) function, enhanced angiogenesis, reduced degree of CM apoptosis, and reduced oxidative stress post MI. There was significantly higher numbers of dividing CM in the infarct zone between 3–9 days post MI (P < 0.001). Mechanistically, we determined that Pkm2 interacts with β-catenin (Ctnnb1) in the cytoplasm of CM, inhibiting Ctnnb1 phosphorylation at serine 552 and tyrosine 333, by Akt. In the absence of Pkm2, Ctnnb1 translocates to the nucleus leading to transcriptional activation of proliferation-associated target genes. All these effects are abrogated by genetic co-deletion of Pkm2 and Ctnnb1. Collectively, this work supports a novel antiproliferative function for Pkm2 in CM through the sequestration of Ctnnb1 in the cytoplasm of CM whereas loss of Pkm2 is essential for CM proliferation. Reducing cardiac Pkm2 expression may provide a useful strategy for cardiac repair after MI in patients.
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This work was supported by grants awarded by the Canadian Institute of Health Research to FB. FB is the recipient of the Canadian Institute of Health Research Phase II Clinician-Scientist Award.
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FB and LH designed research; DG, SC, KD, and LH performed research; FB and LH analyzed data; FB and LH wrote the manuscript.
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Hauck, L., Dadson, K., Chauhan, S. et al. Inhibiting the Pkm2/b-catenin axis drives in vivo replication of adult cardiomyocytes following experimental MI. Cell Death Differ 28, 1398–1417 (2021). https://doi.org/10.1038/s41418-020-00669-9
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DOI: https://doi.org/10.1038/s41418-020-00669-9
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