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Myc controls transcriptional regulation of cardiac metabolism and mitochondrial biogenesis in response to pathological stress in mice
Preeti Ahuja, … , Michael Portman, W. Robb MacLellan
Preeti Ahuja, … , Michael Portman, W. Robb MacLellan
Published April 1, 2010
Citation Information: J Clin Invest. 2010;120(5):1494-1505. https://doi.org/10.1172/JCI38331.
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Research Article Cardiology Article has an altmetric score of 3

Myc controls transcriptional regulation of cardiac metabolism and mitochondrial biogenesis in response to pathological stress in mice

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Abstract

In the adult heart, regulation of fatty acid oxidation and mitochondrial genes is controlled by the PPARγ coactivator–1 (PGC-1) family of transcriptional coactivators. However, in response to pathological stressors such as hemodynamic load or ischemia, cardiac myocytes downregulate PGC-1 activity and fatty acid oxidation genes in preference for glucose metabolism pathways. Interestingly, despite the reduced PGC-1 activity, these pathological stressors are associated with mitochondrial biogenesis, at least initially. The transcription factors that regulate these changes in the setting of reduced PGC-1 are unknown, but Myc can regulate glucose metabolism and mitochondrial biogenesis during cell proliferation and tumorigenesis in cancer cells. Here we have demonstrated that Myc activation in the myocardium of adult mice increases glucose uptake and utilization, downregulates fatty acid oxidation by reducing PGC-1α levels, and induces mitochondrial biogenesis. Inactivation of Myc in the adult myocardium attenuated hypertrophic growth and decreased the expression of glycolytic and mitochondrial biogenesis genes in response to hemodynamic load. Surprisingly, the Myc-orchestrated metabolic alterations were associated with preserved cardiac function and improved recovery from ischemia. Our data suggest that Myc directly regulates glucose metabolism and mitochondrial biogenesis in cardiac myocytes and is an important regulator of energy metabolism in the heart in response to pathologic stress.

Authors

Preeti Ahuja, Peng Zhao, Ekaterini Angelis, Hongmei Ruan, Paavo Korge, Aaron Olson, Yibin Wang, Eunsook S. Jin, F. Mark Jeffrey, Michael Portman, W. Robb MacLellan

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Figure 4

Myc is required for induction of the LDHA gene in an E-box–dependent manner in response to hypertrophic agonists.

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Myc is required for induction of the LDHA gene in an E-box–dependent man...
(A) Total ventricular RNA from NRVMs infected with no virus (Ctrl), AdLacZ, or AdMyc was analyzed by semiquantitative PCR for glycolytic genes (ENO-1α and LDHA) or β-actin control. (B) Schematic diagram depicting the wild-type LDHA promoter containing 2 E-boxes (E1 and E2) and 2 HIF-1α–binding (H1 and H2) sites. The E2 and H2 binding sites overlap. The mutation of the 5ι-E-box, mE1, is also shown. (C) NRVMs were transfected with either LDHA-WT or LDHA-mE1 infected with control or Myc-expressing vector. The relative luciferase activities are shown for the wild-type or mutated LDHA promoter. *P < 0.01 for LDHA-WT + Myc versus LDHA-WT without Myc or LDHA-mE1 + Myc. (D) NRVMs were transfected with either LDHA-WT or mutated promoter LDHA-mE1 and stimulated with vehicle or ET-1 for 16 hours. *P < 0.001 versus LDHA-WT without ET-1; **P < 0.01 versus LDHA-mE1 + ET-1. All data shown are representative of at least 3 independent experiments.

Copyright © 2025 American Society for Clinical Investigation
ISSN: 0021-9738 (print), 1558-8238 (online)

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