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A PKM2 signature in the failing heart
Meredith L Rees1, Janani Subramaniam1, Yuanteng Li1
1Department of Internal Medicine, Division of Cardiology, The University of Texas Medical School at Houston, 6431 Fannin Street, MSB 1.220, Houston, TX 77030, USA.
Abstract:
A salient feature of the failing heart is metabolic remodeling towards predominant glucose metabolism and activation of the fetal gene program. Sunitinib is a multitargeted receptor tyrosine kinase inhibitor used for the treatment of highly vascularized tumors. In diabetic patients, sunitinib significantly decreases blood glucose. However, a considerable proportion of sunitinib-treated patients develop cardiac dysfunction or failure. We asked whether sunitinib treatment results in shift towards glycolysis in the heart. Glucose uptake by the heart was increased fivefold in mice treated with sunitinib. Transcript analysis by qPCR revealed an induction of genes associated with glycolysis and reactivation of the fetal gene program. Additionally, we observed a shift in the enzyme pyruvate kinase from the adult M1 (PKM1) isoform to the fetal M2 (PKM2) isoform, a hallmark of the Warburg Effect. This novel observation led us to examine whether a similar shift occurs in human heart failure. Examination of tissue from patients with heart failure similarly displayed an induction of PKM2. Moreover, this phenomenon was partially reversed following mechanical unloading. We propose that pyruvate kinase isoform switching represents a novel feature of the fetal gene program in the failing heart.
Insights
Sunitinib treatment shifts heart metabolism toward glucose use and reactivates fetal genes, including pyruvate kinase M2 (PKM2). This metabolic shift is also observed in human heart failure.
Area of Science:
- Cardiology
- Molecular Biology
- Biochemistry
Background:
- Heart failure is characterized by metabolic shifts to glucose utilization and fetal gene activation.
- Sunitinib, a tyrosine kinase inhibitor, can cause cardiac dysfunction despite its glucose-lowering effects in diabetics.
Purpose of the Study:
- To investigate if sunitinib induces a metabolic shift towards glycolysis in the heart.
- To determine if pyruvate kinase isoform switching occurs in sunitinib-treated hearts and human heart failure.
Main Methods:
- Mice were treated with sunitinib to assess cardiac glucose uptake and gene expression via qPCR.
- Pyruvate kinase (PK) isoform expression was analyzed, comparing adult PKM1 to fetal PKM2.
- Human heart failure tissues were examined for PKM2 induction.
Main Results:
- Sunitinib treatment increased cardiac glucose uptake fivefold in mice.
- Gene expression analysis revealed induction of glycolytic genes and fetal gene program reactivation.
- A shift from PKM1 to PKM2 was observed in mice and in human heart failure tissues, partially reversed by mechanical unloading.
Conclusions:
- Sunitinib induces a metabolic switch to glycolysis and fetal gene reactivation in the heart.
- Pyruvate kinase isoform switching (PKM1 to PKM2) is a novel feature of the failing heart, linked to the fetal gene program.
- This phenomenon may contribute to sunitinib-induced cardiac dysfunction and is a potential hallmark of heart failure progression.
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