PKM1 Exerts Critical Roles in Cardiac Remodeling Under Pressure Overload in the Heart

Abstract

Background: Metabolic remodeling precedes most alterations during cardiac hypertrophic growth under hemodynamic stress. The elevation of glucose utilization has been recognized as a hallmark of metabolic remodeling. However, its role in cardiac hypertrophic growth and heart failure in response to pressure overload remains to be fully illustrated. Here, we aimed to dissect the role of cardiac PKM1 (pyruvate kinase muscle isozyme 1) in glucose metabolic regulation and cardiac response under pressure overload. Methods: Cardiac specific deletion of PKM1 was achieved by crossing the floxed PKM1 mouse model with the cardiomyocyte-specific Cre transgenic mouse. PKM1 transgenic mice were generated under the control of tetracycline response elements, and cardiac specific overexpression of PKM1 was induced by doxycycline administration in adult mice. Pressure overload was triggered by transverse aortic constriction (TAC). Primary neonatal rat ventricular myocytes were used to dissect molecular mechanisms. Moreover, metabolomics and NMR spectroscopy analyses were conducted to determine cardiac metabolic flux in response to pressure overload. Results: We found that PKM1 expression is reduced in failing human and mouse hearts. Importantly, cardiomyocyte-specific deletion of PKM1 exacerbates cardiac dysfunction and fibrosis in response to pressure overload. Inducible overexpression of PKM1 in cardiomyocytes protects the heart against TAC-induced cardiomyopathy and heart failure. At the mechanistic level, PKM1 is required for the augmentation of glycolytic flux, mitochondrial respiration, and ATP production under pressure overload. Furthermore, deficiency of PKM1 causes a defect in cardiomyocyte growth and a decrease in pyruvate dehydrogenase complex activity at both in vitro and in vivo levels. Conclusions: These findings suggest that PKM1 plays an essential role in maintaining a homeostatic response in the heart under hemodynamic stress.

The isoforms of pyruvate kinase act as nutrient sensors for the β-cell KATP channel

“…1c ). In both strains this partial compensation is expected since PKm1 and PKm2 are alternative splice variants of the Pkm gene 14,19 . Pck2 f/f mice were generated de novo ( Fig.…”

“…We generated β-cell specific PKm1 and PKm2 knockout mice by breeding Ins1-Cre mice (Thorens et al, 2015) with Pkm1 f/f mice (Davidson et al, 2021; Li et al, 2021) (PKm1-βKO) or Pkm2 f/f mice (Israelsen et al, 2013) (PKm2-βKO). PKm1 protein was reduced by 71% in PKm1-βKO islets, while PKm2 increased by 46% compared to littermate Ins1-Cre controls (Figure 1b).…”

“…β-cell specific PKm1 and PKm2 knockout mice were generated by breeding Ins1-Cre (Thorens et al, 2015) mice ( B6(Cg)-Ins1 tm1.1(cre)Thor /J , Jackson Laboratory #026801) with Pkm1 f/f mice (Davidson et al, 2021; Li et al, 2021, p. 1) provided by Matthew Vander Heiden (MIT) or Pkm2 f/f mice (Israelsen et al, 2013) (B6;129S- Pkm tm1.1Mgvh /J, Jackson Laboratory #024408) after 10 generations of backcrossing to C57BL6/J mice (Jackson Laboratory). Pck2 f/f mice were generated de novo by the University of Wisconsin-Madison Genome Editing and Animal Model core.…”

“…Comparatively, expression of PKm2 protein fell by 94% in PKm2-βKO islets, while PKm1 increased by 29% (Figure 1c). In both strains this partial compensation is expected since PKm1 and PKm2 are alternative splice variants of the Pkm gene (19,24). Pck2 f/f mice were generated de novo (Figure S2) and crossed with Ucn3-Cre mice to facilitate postnatal β-cell deletion without the need for tamoxifen (25).…”

“…Pharmacologic PK activators (PKa), which lower the K m of PKm2 for PEP and increase the V max (Anastasiou et al, 2012), increase the frequency of glucose-stimulated Ca 2+ and ATP/ADP oscillations and potentiate nutrient-stimulated insulin secretion from rodent and human islets (Abulizi et al, 2020; Lewandowski et al, 2020). Much less is known about the PKm1 isoform, which due to its constitutive (FBP-insensitive) activity might be ideal in situations of high oxidative workload, as in cardiac myocytes (Li et al, 2021). β-cells may shift their reliance upon different PK isoforms throughout the oscillatory cycle, as the levels of glycolytic FBP rise during Mito Cat and fall during Mito Ox (Lewandowski et al, 2020; Merrins et al, 2016, 2013).…”