The mTOR/p70<sup>S6K</sup>Signal Transduction Pathway Plays a Role in Cardiac Hypertrophy and Influences Expression of Myosin Heavy Chain Genes in vivo

Boluyt, Marvin O.; Li, Zhao Bo; Loyd, Amy; Scalia, Antony F.; Cirrincione, Georgina M.; Jackson, Rebecca R.

doi:10.1023/b:card.0000041245.61136.56

Cited by 48 publications

(50 citation statements)

References 39 publications

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“…However, PA can also activate mTORC1, leading to the downstream activation of p70S6 kinase ( 58,59 ), which phosphorylates and activates S6 ribosomal protein to promote cell growth ( 58,59 ). In fact, activation of mTORC1-p70S6 kinase leads to cardiac hypertrophy ( 79 ). We now show that there is an increase in signaling downstream of mTOR, i.e., increased p70S6 kinase phosphorylation in combination with a 14-fold increase in S6 ribosomal protein activation.…”

Section: Examination Of the Downstream Signaling Effects Of Aberrant mentioning

confidence: 67%

Relationship of glucose and oleate metabolism to cardiac function in lipin-1 deficient (fld) mice

Kok

Kienesberger

Dyck

et al. 2012

Journal of Lipid Research

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of cardiac ATP production ( 1 ). FAs are also incorporated into triacylglycerol (TG), which is stored in lipid droplets. Cardiac TG turnover is rapid ( 2 ) and FAs released from TG can contribute up to 10-20% of ATP production ( 3 ). Plasma FA and TG levels rise in insulin resistance and diabetes ( 4, 5 ), and cardiac FA utilization can increase to supply as much as 90% of ATP ( 6, 7 ). Despite this increase in FAO, FA uptake can exceed the ability of the heart to utilize FAs, leading to excess accumulation of TG in cardiomyocytes ( 6-9 ). The compensatory changes that occur in response to excessive FA availability eventually become maladaptive, and the heart is locked in a pathological and infl exible metabolic state that contributes to cardiac dysfunction ( 6, 7, 10 ). As such, maintenance of metabolic fl exibility is essential for normal cardiac function. Whereas many proteins have been identifi ed to contribute to cardiac FA uptake and metabolism ( 1, 10 ), relatively little information is available about the role of lipin-1 in the heart. Lipin-1 is an important protein involved in regulating both TG synthesis and FAO in other organs ( 11 ).Instead of being considered as mutually antagonistic processes, FAO and TG synthesis are now widely viewed as being companion pathways because augmenting cardiac TG synthesis increases FAO ( 12 ). Moreover, FAs released through lipolysis of endogenous TG stores contribute signifi cantly to FAO ( 3,13 ). Lipin-1 could play a prominent role in this regulation as it is a bifunctional protein involved in regulating both TG synthesis and FAO in the The constant requirement for ATP in the beating heart is satisfi ed by the utilization of diverse substrates, such as fatty acids (FA), glucose, lactate, ketones, and amino acids, with FA oxidation (FAO) providing the majority (50-75%)

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Section: Examination Of the Downstream Signaling Effects Of Aberrant mentioning

confidence: 67%

Relationship of glucose and oleate metabolism to cardiac function in lipin-1 deficient (fld) mice

Kok

Kienesberger

Dyck

et al. 2012

Journal of Lipid Research

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“…11,12,14 As in our study, ␤-MHC was reported to be increased after rapamycin, suggesting a stress response of the cardiomyocytes. 12,15 In contrast, studies with rapamycin reported either preserved function or protection from overload-induced dysfunction. 11,12 This discrepancy might be explained by the dosing and timing of the rapamycin treatment.…”

Section: Discussionmentioning

confidence: 99%

“…[11][12][13][14][15] However, other studies have challenged the importance of mTOR-mediated protein synthesis and growth. For example, deletion of the ribosomal S6 kinases, direct downstream effectors of mTOR, did not attenuate pathological, physiological, or insulin-like growth factor receptor-induced cardiac hypertrophy.…”

Section: Clinical Perspective On P 1082mentioning

confidence: 99%

Cardiac Raptor Ablation Impairs Adaptive Hypertrophy, Alters Metabolic Gene Expression, and Causes Heart Failure in Mice

et al. 2011

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Background-Cardiac hypertrophy involves growth responses to a variety of stimuli triggered by increased workload. It is an independent risk factor for heart failure and sudden death. Mammalian target of rapamycin (mTOR) plays a key role in cellular growth responses by integrating growth factor and energy status signals. It is found in 2 structurally and functionally distinct multiprotein complexes called mTOR complex (mTORC) 1 and mTORC2. The role of each of these branches of mTOR signaling in the adult heart is currently unknown. Methods and Results-We generated mice with deficient myocardial mTORC1 activity by targeted ablation of raptor, which encodes an essential component of mTORC1, during adulthood. At 3 weeks after the deletion, atrial and brain natriuretic peptides and ␤-myosin heavy chain were strongly induced, multiple genes involved in the regulation of energy metabolism were altered, but cardiac function was normal. Function deteriorated rapidly afterward, resulting in dilated cardiomyopathy and high mortality within 6 weeks. Aortic banding-induced pathological overload resulted in severe dilated cardiomyopathy already at 1 week without a prior phase of adaptive hypertrophy. The mechanism involved a lack of adaptive cardiomyocyte growth via blunted protein synthesis capacity, as supported by reduced phosphorylation of ribosomal S6 kinase 1 and 4E-binding protein 1. In addition, reduced mitochondrial content, a shift in metabolic substrate use, and increased apoptosis and autophagy were observed. Conclusions-Our results demonstrate an essential function for mTORC1 in the heart under physiological and pathological conditions and are relevant for the understanding of disease states in which the insulin/insulin-like growth factor signaling axis is affected such as diabetes mellitus and heart failure or after cancer therapy. (Circulation. 2011;123:1073-1082.)Key Words: heart failure Ⅲ hypertrophy Ⅲ myocardial metabolism Ⅲ signal transduction A lthough cardiac hypertrophy is a growth response that initially normalizes wall tension, it is associated with an unfavorable outcome: Affected patients are threatened with sudden death or progression to heart failure. 1 Much research is therefore aimed at understanding myocardial growth regulation, and in this setting, the insulin-like growth factor/PI3-kinase/Akt signaling cascade has been studied extensively. 2,3 Experiments with cultured cardiomyocytes have suggested that downstream of Akt, mammalian target of rapamycin (mTOR) mediates responses to pathological stimuli. 4,5 mTOR is an evolutionary conserved Ser/Thr kinase known to control cell growth. 6 Nutrient, energy, and growth factor shortage will impair mTOR activity, resulting in diverse effects, including the slowdown of macromolecule synthesis, enhanced autophagy, and activation of nutrient-or stressresponsive transcription factors. mTOR is found in 2 structurally and functionally distinct multiprotein complexes called mTOR complex 1 (mTORC1) and mTORC2. The 2 best-characterized substrates of mTORC1 ...

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“…Role of mTOR inhibition on LVH: Some experimental studies have demonstrated the efficacy of the mTOR inhibitor SRL in the regression of LVH in transverse aortic constriction animal models. 8,12) The rationale of these studies lies in the inhibitory effect of SRL on the mTOR/p70 S6 kinase signal transduction pathway, 9) which plays a central role in cardiac hypertrophy.…”

Section: Discussionmentioning

confidence: 99%

“…6) The mammalian target of rapamycin (mTOR) pathway plays a central role in regulating mRNA translation and cell growth, 7) and an mTOR inhibitor, sirolimus (SRL), has been demonstrated to decrease LV mass (LVM) in experimental animal models. [8][9][10][11][12] Clinical studies also showed that SRL had an advantage in the improvement of LVH compared with conventional calcineurin inhibitors (CNI) when used as an immunosuppressant in heart or kidney transplant recipients. [13][14][15] However, little is known about how the next generation mTOR inhibitor derivative everolimus (EVL) affects LVM.…”

Section: Eft Ventricular Hypertrophy (Lvh) Is Observed In Pa-mentioning

confidence: 99%

Everolimus Attenuates Myocardial Hypertrophy and Improves Diastolic Function in Heart Transplant Recipients

et al. 2016

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SummaryEverolimus (EVL), one of the mammalian targets of rapamycin, is a next generation immunosuppressant that may have accessory anti-proliferative effects in heart transplant (HTx) recipients. However, little is known about the clinical relationship between EVL and regression of cardiac hypertrophy. A total of 42 HTx recipients received EVL therapy at post-HTx 150 days on median and had been followed at our institute for > 1 year between 2008 and 2014 [EVL (+) group]. We also observed 18 patients without EVL from post-HTx 150 days for 1 year [EVL (-) group]. There were no significant differences in baseline variables between the two groups. Left ventricular mass index (LVMI) and the ratio of early transmitral filling velocity to the peak early diastolic mitral annular motion velocity (E/e') decreased significantly during 1-year EVL treatment compared with the EVL (-) group. There were no differences in blood pressure and medications between the 2 groups. Improvement of LVMI and the E/e' ratio was not associated with trough levels of calcineurin inhibitors or EVL, but correlated with each baseline value. In conclusion, this EVL-incorporated immunosuppressant regimen attenuated cardiac hypertrophy as well as diastolic dysfunction in HTx recipients. (Int Heart J 2016; 57: 204-210)

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The mTOR/p70^S6KSignal Transduction Pathway Plays a Role in Cardiac Hypertrophy and Influences Expression of Myosin Heavy Chain Genes in vivo

Abstract: The data suggest that an intact mTOR signaling pathway is required for rapid hypertrophic growth of the heart in vivo. Moreover, the data suggest a novel link between the mTOR/p70(S6K) signal transduction pathway and pretranslational control of myosin gene expression in the heart.

Cited by 48 publications

References 39 publications

Relationship of glucose and oleate metabolism to cardiac function in lipin-1 deficient (fld) mice

Relationship of glucose and oleate metabolism to cardiac function in lipin-1 deficient (fld) mice

Cardiac Raptor Ablation Impairs Adaptive Hypertrophy, Alters Metabolic Gene Expression, and Causes Heart Failure in Mice

Everolimus Attenuates Myocardial Hypertrophy and Improves Diastolic Function in Heart Transplant Recipients

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The mTOR/p70S6KSignal Transduction Pathway Plays a Role in Cardiac Hypertrophy and Influences Expression of Myosin Heavy Chain Genes in vivo

Abstract: The data suggest that an intact mTOR signaling pathway is required for rapid hypertrophic growth of the heart in vivo. Moreover, the data suggest a novel link between the mTOR/p70(S6K) signal transduction pathway and pretranslational control of myosin gene expression in the heart.

Cited by 48 publications

References 39 publications

Relationship of glucose and oleate metabolism to cardiac function in lipin-1 deficient (fld) mice

Relationship of glucose and oleate metabolism to cardiac function in lipin-1 deficient (fld) mice

Cardiac Raptor Ablation Impairs Adaptive Hypertrophy, Alters Metabolic Gene Expression, and Causes Heart Failure in Mice

Everolimus Attenuates Myocardial Hypertrophy and Improves Diastolic Function in Heart Transplant Recipients

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The mTOR/p70^S6KSignal Transduction Pathway Plays a Role in Cardiac Hypertrophy and Influences Expression of Myosin Heavy Chain Genes in vivo