title: Myc controls transcriptional regulation of cardiac metabolism and mitochondrial biogenesis in response to pathological stress in mice.
abstract: In the adult heart, regulation of fatty acid oxidation and mitochondrial genes is controlled by the PPARgamma 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-1alpha 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.affiliation: Department of Medicine, The Cardiovascular Research Laboratories, David Geffen School of Medicine at UCLA, Los Angeles, California 90095-1760,, USA.
authors.forename: Preeti
authors.initials: P
authors.lastname: Ahuja
authors.forename: Peng
authors.initials: P
authors.lastname: Zhao
authors.forename: Ekaterini
authors.initials: E
authors.lastname: Angelis
authors.forename: Hongmei
authors.initials: H
authors.lastname: Ruan
authors.forename: Paavo
authors.initials: P
authors.lastname: Korge
authors.forename: Aaron
authors.initials: A
authors.lastname: Olson
authors.forename: Yibin
authors.initials: Y
authors.lastname: Wang
authors.forename: Eunsook S
authors.initials: ES
authors.lastname: Jin
authors.forename: F Mark
authors.initials: FM
authors.lastname: Jeffrey
authors.forename: Michael
authors.initials: M
authors.lastname: Portman
authors.forename: W Robb
authors.initials: WR
authors.lastname: Maclellan
mesh_terms: D000818:Animals; D049109:Cell Proliferation; D005227:Fatty Acids / Q000378:metabolism; D005786:Gene Expression Regulation; D005947:Glucose / Q000378:metabolism; D006439:Hemodynamics; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D008928:Mitochondria / Q000378:metabolism*; D017202:Myocardial Ischemia; D032383:Myocytes, Cardiac / Q000166:cytology*; D009369:Neoplasms / Q000378:metabolism; D010100:Oxygen / Q000737:chemistry / Q000378:metabolism; D016271:Proto-Oncogene Proteins c-myc / Q000378:metabolism*; D014157:Transcription Factors / Q000378:metabolism*; D014158:Transcription, Genetic; D015533:Transcriptional Activation
chemical_list: D005227:Fatty Acids; D016271:Proto-Oncogene Proteins c-myc; D014157:Transcription Factors; C111264:peroxisome-proliferator-activated receptor-gamma coactivator-1; D005947:Glucose; D010100:Oxygen