Mammalian Target of Rapamycin and Protein Kinase A Signaling Mediate the Cardiac Transcriptional Response to Glutamine

Xia, Yang; Wen, Hong; Young, Martin E.; Guthrie, Paul D.; Taegtmeyer, Heinrich; Kellems, Rodney E.

doi:10.1074/jbc.m208500200

Cited by 62 publications

(44 citation statements)

References 59 publications

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“…19 We have previously shown that glutamine administration causes hypertrophy of cardiomyocytes with activation of mTOR. 20 We speculate that atrophic remodeling of the heart may result in an accumulation of intracellular amino acids secondary to breakdown by the UPP, which subsequently leads to the activation of mTOR.…”

Section: Activation Of Mtor In Atrophymentioning

confidence: 99%

Atrophic Remodeling of the Heart In Vivo Simultaneously Activates Pathways of Protein Synthesis and Degradation

et al. 2003

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Background-Mechanical unloading of the heart results in atrophic remodeling. In skeletal muscle, atrophy is associated with inactivation of the mammalian target of rapamycin (mTOR) pathway and upregulation of critical components of the ubiquitin proteosome proteolytic (UPP) pathway. The hypothesis is that mechanical unloading of the mammalian heart has differential effects on pathways of protein synthesis and degradation. Methods and Results-In a model of atrophic remodeling induced by heterotopic transplantation of the rat heart, we measured gene transcription, protein expression, polyubiquitin content, and regulators of the mTOR pathway at 2, 4, 7, and 28 days. In atrophic hearts, there was an increase in polyubiquitin content that peaked at 7 days and decreased by 28 days. Furthermore, gene and protein expression of UbcH2, a ubiquitin conjugating enzyme, was also increased early in the course of unloading. Transcript levels of TNF-␣, a known regulator of UbcH2-dependent ubiquitin conjugating activity, were upregulated early and transiently in the atrophying rat heart. Unexpectedly, p70S6K and 4EBP1, downstream components of mTOR, were activated in atrophic rat heart. This activation was independent of Akt, a known upstream regulator of mTOR. Rapamycin treatment of the unloaded rat hearts inhibited the activation of p70S6K and 4EBP1 and subsequently augmented atrophy in these hearts compared with vehicle-treated, unloaded hearts. Conclusions-Atrophy of the heart, secondary to mechanical unloading, is associated with early activation of the UPP. The simultaneous activation of the mTOR pathway suggests active remodeling, involving both protein synthesis and degradation.

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Section: Activation Of Mtor In Atrophymentioning

confidence: 99%

Atrophic Remodeling of the Heart In Vivo Simultaneously Activates Pathways of Protein Synthesis and Degradation

et al. 2003

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“…The latter is an important intracellular transducer of a growth-related signaling pathway, which is rapamycinsensitive and dependent on activation of a 70 kDa S6 kinase (p70 S6K ) (Xia et al, 2003). The S6 phosphorylation is known to be required for the translation of the terminal oligopyrimidine family of RNAs that contain an oligopyrimidine tract upstream of their transcription-initiation site.…”

Section: Cell Proliferationmentioning

confidence: 99%

“…Glutamine may serve as an energy source also for the heart. Xia et al (2003) have demonstrated that glutamine can induce cardiomyocyte growth and maturation accompanied by an increase in mRNA levels of contractile proteins including a-myosin heavy chain (a-MHC) and cardiac a-actin. This was associated with physiological hypertrophy.…”

Section: Protein Synthesis and Degradationmentioning

confidence: 99%

“…Glutamine can stimulate expression of adenylosuccinate synthase (ADSS-1), which can regulate cell proliferation via activation of protein kinase A and mTOR in neonatal rat cardiomyocytes (Xia et al, 2003). The latter is an important intracellular transducer of a growth-related signaling pathway, which is rapamycinsensitive and dependent on activation of a 70 kDa S6 kinase (p70 S6K ) (Xia et al, 2003).…”

Section: Cell Proliferationmentioning

confidence: 99%

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Molecular mechanisms of glutamine action

Curi

Lagranha

Doi

et al. 2005

Journal Cellular Physiology

416

300

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Glutamine is the most abundant free amino acid in the body and is known to play a regulatory role in several cell specific processes including metabolism (e.g., oxidative fuel, gluconeogenic precursor, and lipogenic precursor), cell integrity (apoptosis, cell proliferation), protein synthesis, and degradation, contractile protein mass, redox potential, respiratory burst, insulin resistance, insulin secretion, and extracellular matrix (ECM) synthesis. Glutamine has been shown to regulate the expression of many genes related to metabolism, signal transduction, cell defense and repair, and to activate intracellular signaling pathways. Thus, the function of glutamine goes beyond that of a simple metabolic fuel or protein precursor as previously assumed. In this review, we have attempted to identify some of the common mechanisms underlying the regulation of glutamine dependent cellular functions.

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“…In rodent, it has been reported that L-glutamine supplementation of a high fat diet attenuates hyperglycaemia and hyperinsulinaemia in C57BL/6J mice (Opara et al, 1996). Moreover, Xia et al (2003) revealed that glutamine, as a major nutrient, could increased abundance of the mRNAs encoding the metabolic enzymes in mouse, muscle carnitine palmitoyl transferase I and muscle adenylosuccinate synthetase. In avian, however, the lipid metabolism is much different from mammal and rodent.…”

Section: Discussionmentioning

confidence: 99%

Effects of glycyl-glutamine on the growth performance and lipid deposition in Yue-Huang broilers

Shu¹,

Gao²,

Zhu³

et al. 2007

J. Anim. Feed Sci.

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To investigate the effects of glycyl-glutamine (Gly-Gln) on the growth performance and body composition in Yue-Huang broilers, two hundreds and seventy 9-d-old birds were randomly allocated to 3 groups of 90 birds each, incorporating 3 cages per group. All the birds were offered a commercial starter feed supplemented with 0, 0.01 or 0.05 mg Gly-Gln per kg for next 5 weeks, then given a commercial grower feed for another 5 weeks. The results showed that Gly-Gln could not only significantly increase the body weight of Yue-Huang broilers but also enhanced breast muscle and leg muscle yields, while it declined abdominal fat percentage in a dose-dependent manner. The concentration of triglyceride and total cholesterol (T-CHO) in serum and that of T-CHO in pectoralis major muscle were reduced with the up-regulated mRNA expression of peroxisome proliferatoractivated receptors α (PPAR-α) and down-regulated transcript levels of acetyl-CoA carboxylase (ACC) and sterol regulatory element binding protein-2 (SREBP-2).

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Mammalian Target of Rapamycin and Protein Kinase A Signaling Mediate the Cardiac Transcriptional Response to Glutamine

Cited by 62 publications

References 59 publications

Atrophic Remodeling of the Heart In Vivo Simultaneously Activates Pathways of Protein Synthesis and Degradation

Atrophic Remodeling of the Heart In Vivo Simultaneously Activates Pathways of Protein Synthesis and Degradation

Molecular mechanisms of glutamine action

Effects of glycyl-glutamine on the growth performance and lipid deposition in Yue-Huang broilers

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