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

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

Research output: Contribution to journalArticlepeer-review

91 Scopus citations

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-1γ 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.

Original languageEnglish (US)
Pages (from-to)1494-1505
Number of pages12
JournalJournal of Clinical Investigation
Volume120
Issue number5
DOIs
StatePublished - May 3 2010

ASJC Scopus subject areas

  • Medicine(all)

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