Faculty, Staff and Student Publications

Language

English

Publication Date

4-1-2026

Journal

Physiological Genomics

DOI

10.1152/physiolgenomics.00319.2025

PMID

41801102

PMCID

PMC13078181

PubMedCentral® Posted Date

4-15-2026

PubMedCentral® Full Text Version

Author MSS

Abstract

Myocardial metabolic flexibility is critical to ensuring the heart's capacity to maintain contraction and cellular functions under rapidly evolving environmental conditions. Although it is a tightly regulated process, loss of metabolic flexibility is often regarded as a contributing factor to heart failure. This study aims to determine the effects of the early response transcription factor nuclear receptor subfamily 4 group A member 2 (NR4A2) on cardiac metabolism and the resulting impact on left ventricular function. A multiomics approach combining the analysis of global ventricular gene expression, genome-wide NR4A2 binding, and untargeted metabolomics was used to track the molecular effects of cardiomyocyte-specific NR4A2 activation in male and female mice over time. Doppler echocardiography was performed in parallel to monitor changes in left ventricular function. We found that NR4A2 acts as a direct transcriptional activator of the genes encoding the glucose transporter type 4 and most glycolytic enzymes. The upregulation of glycolysis was accompanied by the inhibition of fatty acid β-oxidation and by activation of glutamine-dependent reductive carboxylation to promote the synthesis of phospholipids. This was further supported by NR4A2-dependent transcriptional regulation of key enzymes in the phosphatidic acid pathway. Rewiring of the Krebs cycle for biosynthetic purposes was followed by a progressive decline in left ventricular contractility. In conclusion, our results expose NR4A2 as a critical component of the cell regulatory machinery governing transcriptional reprogramming of cardiac metabolism under stress. These findings provide a conceptual framework illustrating how an acute adaptive metabolic response may become maladaptive on the long-term.

Keywords

Animals, Male, Mice, Female, Phospholipids, Glycolysis, Myocardium, Myocytes, Cardiac, Mice, Inbred C57BL, Ventricular Function, Left, Glucose Transporter Type 4

Published Open-Access

yes

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