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

Ahuja, Preeti; Zhao, Peng; Angelis, Ekaterini; Ruan, Hongmei; Kôrge, Paavo; Olson, Aaron K.; Wang, Yibin; Jin, Eunsook S.; Jeffrey, F. M H; Portman, Michael A.; MacLellan, W. Robb

doi:10.1172/jci38331

Cited by 136 publications

(143 citation statements)

References 80 publications

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“…Most of the studies on c-Myc-transcribed genes are in the context of cancer, although some studies have clearly demonstrated its overexpression following injury (51). Although cancer and injury may share certain biological characteristics such as hypoxia and inflammation, the regulation of genes following injury is expected to have a different signature; the c-Mycmodulated spectrum of genes has not been clearly defined (38,48,52).…”

Section: Discussionmentioning

confidence: 99%

Resveratrol Improves Cardiac Contractility following Trauma-Hemorrhage by Modulating Sirt1

Jian

Yang

Chaudry

et al. 2011

Mol Med

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Mitochondria play a critical role in metabolic homeostasis of a cell. Our recent studies, based on the reported interrelationship between c-Myc and Sirt1 (mammalian orthologue of yeast sir2 [silent information regulator 2]) expression and their role in mitochondrial biogenesis and function, demonstrated a significant downregulation of Sirt1 protein expression and an upregulation of c-Myc following trauma-hemorrhage (T-H). Activators of Sirt1 are known to improve mitochondrial function and the naturally occurring polyphenol resveratrol (RSV) has been shown to significantly increase Sirt1 activity by increasing its affinity to both NAD+ and the acetylated substrate. In this study we tested the salutary effect of RSV following T-H and its influence on Sirt1 expression. Rats were subjected to T-H or sham operation. RSV (8 mg/kg body weight, intravenously) or vehicle was administered 10 min after the onset of resuscitation, and the rats were killed 2 h following resuscitation. Sirtinol, a Sirt1 inhibitor, was administered 5 min prior to RSV administration. Cardiac contractility (±dP/dt) was measured and heart tissue was tested for Sirt1, Pgc-1α, c-Myc, cytosolic cytochrome C expression and ATP level. Left ventricular function, after T-H, was improved (P < 0.05) following RSV treatment, with significantly elevated expression of Sirt1 (P < 0.05) and Pgc-1α (P < 0.05), and decreased c-Myc (P < 0.05). We also observed significantly higher cardiac ATP content, declined cytosolic cytochrome C and decreased plasma tumor necrosis factor-α in the T-H-RSV group. The salutary effect due to RSV was abolished by sirtinol, indicating a Sirt1-mediated effect. We conclude that RSV may be a useful adjunct to resuscitation fluid following T-H.

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Section: Discussionmentioning

confidence: 99%

Resveratrol Improves Cardiac Contractility following Trauma-Hemorrhage by Modulating Sirt1

Jian

Yang

Chaudry

et al. 2011

Mol Med

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“…HIF and c-Myc act on multiple targets to regulate carbon metabolism and act in concert to fine tune adaptive responses to hypoxic environment (52). In pathological stress, c-Myc regulates the increased metabolic energy demand, then mitochondrial biogenesis (45). Additionally, the c-Myc protein level has been shown to increase markedly after hypoxia and ischemia (53).…”

Section: Discussionmentioning

confidence: 99%

Aging Influences Cardiac Mitochondrial Gene Expression and Cardiovascular Function following Hemorrhage Injury

Jian

Yang

Chen

et al. 2010

Mol Med

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Cardiac dysfunction and mortality associated with trauma and sepsis increase with age. Mitochondria play a critical role in the energy demand of cardiac muscles, and thereby on the function of the heart. Specific molecular pathways responsible for mitochondrial functional alterations after injury in relation to aging are largely unknown. To further investigate this, 6-and 22-monthold rats were subjected to trauma-hemorrhage (T-H) or sham operation and euthanized following resuscitation. Left ventricular tissue was profiled using our custom rodent mitochondrial gene chip (RoMitochip). Our experiments demonstrated a declined left ventricular performance and decreased alteration in mitochondrial gene expression with age following T-H and we have identified c-Myc, a pleotropic transcription factor, to be the most upregulated gene in 6-and 22-month-old rats after T-H. Following T-H, while 142 probe sets were altered significantly (39 up and 103 down) in 6-month-old rats, only 66 were altered (30 up and 36 down) in 22-month-old rats; 36 probe sets (11 up and 25 down) showed the same trend in both groups. The expression of c-Myc and cardiac death promoting gene Bnip3 were increased, and Pgc1-α and Ppar-α a decreased following T-H. Eleven tRNA transcripts on mtDNA were upregulated following T-H in the aged animals, compared with the sham group. Our observations suggest a cmyc-regulated mitochondrial dysfunction following T-H injury and marked decrease in age-dependent changes in the transcriptional profile of mitochondrial genes following T-H, possibly indicating cellular senescence. To our knowledge, this is the first report on mitochondrial gene expression profile following T-H in relation to aging.

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“…These changes are associated with diminution of Ppargc1a and Esrra expression (31,32). The signals leading to their down-regulation during heart failure are still elusive (33), although MYC has been proposed as a potential upstream repressor of Ppargc1a transcription (34).…”

Section: Dissection Of Moribund Med30mentioning

confidence: 99%

Lethal mitochondrial cardiomyopathy in a hypomorphic Med30 mouse mutant is ameliorated by ketogenic diet

Krebs¹,

Fan

Chen

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

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Deficiencies of subunits of the transcriptional regulatory complex Mediator generally result in embryonic lethality, precluding study of its physiological function. Here we describe a missense mutation in Med30 causing progressive cardiomyopathy in homozygous mice that, although viable during lactation, show precipitous lethality 2-3 wk after weaning. Expression profiling reveals pleiotropic changes in transcription of cardiac genes required for oxidative phosphorylation and mitochondrial integrity. Weaning mice to a ketogenic diet extends viability to 8.5 wk. Thus, we establish a mechanistic connection between Mediator and induction of a metabolic program for oxidative phosphorylation and fatty acid oxidation, in which lethal cardiomyopathy is mitigated by dietary intervention.heart | metabolism | peroxisome proliferator-activated receptor-γ coactivator-1α

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

Cited by 136 publications

References 80 publications

Resveratrol Improves Cardiac Contractility following Trauma-Hemorrhage by Modulating Sirt1

Resveratrol Improves Cardiac Contractility following Trauma-Hemorrhage by Modulating Sirt1

Aging Influences Cardiac Mitochondrial Gene Expression and Cardiovascular Function following Hemorrhage Injury

Lethal mitochondrial cardiomyopathy in a hypomorphic Med30 mouse mutant is ameliorated by ketogenic diet

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