Prenatal Mechanistic Target of Rapamycin Complex 1 (m TORC1) Inhibition by Rapamycin Treatment of Pregnant Mice Causes Intrauterine Growth Restriction and Alters Postnatal Cardiac Growth, Morphology, and Function

Hennig, Maria; Fiedler, Saskia; Jux, Christian; Thierfelder, Ludwig; Drenckhahn, Jörg‐Detlef

doi:10.1161/jaha.117.005506

Cited by 26 publications

(29 citation statements)

References 53 publications

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“…mTOR acts as a positive regulator of system A, system L, and taurine placental amino acid transporter activity, all of which are necessary for amino acid transport to the fetus and thus fetal growth. Its role in human fetal growth is not well established, but intrauterine growth restriction has been described in mouse models . mTOR inhibitors are generally well tolerated in young children especially if long‐term treatment is not needed .…”

Section: Discussionmentioning

confidence: 99%

“…33 Its role in human fetal growth is not well established, but intrauterine growth restriction has been described in mouse models. 34 mTOR inhibitors are generally well tolerated in young children especially if long-term treatment is not needed. 35 One study of 18 children specifically evaluated the growth of children on everolimus until age 3, and except for in one child, there was no negative impact of everolimus on growth rate.…”

Section: Growth Restrictionmentioning

confidence: 99%

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Fetal cardiac rhabdomyomas treated with maternal sirolimus

Pluym

Sklansky

et al. 2020

Prenatal Diagnosis

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Objective To review the pathophysiology of rhabdomyomas and the emerging option of prenatal treatment of fetal cardiac rhabdomyomas. Methods We present a case of fetal rhabdomyomas causing significant hemodynamic compromise that received in utero treatment of maternal sirolimus. Genetic amniocentesis confirmed a TSC2 mutation. A treatment program was initiated with a 10‐mg loading dose titrated to a goal maternal trough of 10 to 15 ng/dL. In order to follow fetal cardiac function, a sophisticated method of speckle tracking echocardiography was used before and after treatment. Obstetric ultrasound was used to monitor fetal growth, and clinical surveillance, echocardiography, and brain MRI were used to monitor postnatal growth and development through 6 months of neonatal life. Results Sirolimus was initiated from 28 to 36 weeks of gestation with improvement of cardiac status. During this period, intrauterine growth restriction developed. Postnatally, the infant has had stable rhabdomyomas and cardiac function without reinitiating sirolimus. Brain MRI demonstrated scattered cortical tubers and subependymal nodules, and the infant has not had seizure‐like activity. At 6 months of age, the infant has achieved appropriate developmental milestones. Conclusion In counseling cases of prenatal onset large obstructing rhabdomyomas and cardiac compromise, in utero sirolimus treatment can be considered.

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Section: Discussionmentioning

confidence: 99%

Section: Growth Restrictionmentioning

confidence: 99%

Fetal cardiac rhabdomyomas treated with maternal sirolimus

Pluym

Sklansky

et al. 2020

Prenatal Diagnosis

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“…mTORC1 activates p70S6 kinase followed by phosphorylation of ribosomal protein S6 whereas mTORC2 activates Akt by phosphorylation at Ser473. Rapamycin, as a commonly used inhibitor of mTOR, was found preferentially inhibits mTORC1 [41], although recent studies indicate that long-term treatment of rapamycin also inhibits mTORC2 [42]. Previous studies suggested that mTORC1 is the dominant complex stimulated by IR injury [43].…”

Section: Discussionmentioning

confidence: 99%

Choline Inhibits Ischemia-Reperfusion-Induced Cardiomyocyte Autophagy in Rat Myocardium by Activating Akt/mTOR Signaling

Hang

Zhao

et al. 2018

Cell Physiol Biochem

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Backgroud/Aims: Growing evidence suggests that both cardiomyocyte apoptosis and excessive autophagy exacerbates cardiac dysfunction during myocardial ischemia-reperfusion (IR). As a precursor of acetylcholine, choline has been found to protect the heart by repressing ischemic cardiomyocyte apoptosis. However, the relationship between choline and cardiomyocyte autophagy is unclear. The present study aimed to investigate whether autophagy was involved in the cardioprotection of choline during IR. Methods: Rats were subjected to 30 min reversible ischemia by ligation of left anterior descending coronary artery followed by reperfusion for 2 h. Choline (5 mg/kg, i.v.) alone or along with rapamycin (5 mg/ kg, i.p.) were injected 30 min before ischemia. Transmission electron microscopy, hematoxylin and eosin (HE) and TUNEL staining were conducted to evaluate the effect of choline on cardiac apoptosis and autophagy. Protein levels of autophagic markers including LC3, beclin-1 and p62 as well as Akt and mammalian target of rapamycin (mTOR) were examined by Western blotting. Results: Myocardial IR-induced cardiac apoptosis and accumulation of autophagosomes was attenuated by choline. Choline treatment significantly ameliorated myocardial IR-induced autophagic activity characterized by repression of beclin-1 over-activation, the reduction of autophagosomes, the LC3-II/LC3-I ratio, and p62 protein abundance. In addition, IR-induced downregulation of p-Akt/mTOR cascade was increased by choline. However, the above functions of choline were abolished by rapamycin. Conclusion: These findings suggest that choline plays a protective role against myocardial IR injury by inhibiting excessive autophagy, which might be associated with the activation of Akt/mTOR pathway. This study provides new mechanistic understanding of cardioprotective effect of choline and suggests novel potential therapeutic targets for cardiac IR injury.

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“…Recent investigations have demonstrated that rapamycin treatment in pregnant mice inhibits cardiac function, growth and mass by mTOR inhibition in heart development [49]. Therefore, we treated neonatal mice with rapamycin in late gestation (starting at 15.5 dpc) to determine the effect of prenatal mTOR inhibition on salivary gland development using rapamycin injection methods developed previously [49,50]. Therefore, we treated neonatal mice with rapamycin in late gestation (starting at 15.5 dpc) to determine the effect of prenatal mTOR inhibition on salivary gland development using rapamycin injection methods developed previously [49,50].…”

Section: Mtor Inhibition By Rapamycin Affects Salivary Gland Developmmentioning

confidence: 99%

“…Mammalian target of rapamycin plays a critical role in growth control and development [2,32,48]. Recent investigations have demonstrated that rapamycin treatment in pregnant mice inhibits cardiac function, growth and mass by mTOR inhibition in heart development [49]. However, it has not been evaluated whether mTOR inhibition by rapamycin injection affects salivary gland development.…”

Section: Mtor Inhibition By Rapamycin Affects Salivary Gland Developmmentioning

confidence: 99%

Role of the mTOR signalling pathway in salivary gland development

et al. 2019

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Development of the salivary gland is characterized by extensive branching morphogenesis. Although various molecules have been implicated in salivary gland development, the role of the mammalian target of rapamycin (mTOR) signalling pathway, including both mTOR complexes 1 and 2 (mTORC1 and 2), in salivary gland development is unknown. Here, we examined protein expression levels related to the mTOR signalling pathway using an ex vivo submandibular salivary gland (SMG) organ culture. We showed that branching buds in the salivary glands were substantially decreased and phosphorylation of mTORC1 signalling pathway related proteins (mTOR, p70 ribosomal protein S6 kinase 1 and eukaryotic initiation factor 4E‐binding protein 1) was inhibited by rapamycin (an mTOR inhibitor). In addition, AKT, which is an upstream protein kinase of mTORC1 and is downstream of mTORC2, is inhibited by LY294002 (a phosphatidylinositol 3‐kinase inhibitor), but not by rapamycin. Moreover, rapamycin‐treated ICR neonatal mice exhibited a reduction in both body weight and salivary glands compared with vehicle‐treated neonatal mice. The present data indicate that the mTOR signalling pathway, including both mTORC1 and mTORC2, plays a critical role in salivary gland development both in ex vivo SMG organ culture and ICR neonatal mice in vivo.

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Prenatal Mechanistic Target of Rapamycin Complex 1 (m TORC1) Inhibition by Rapamycin Treatment of Pregnant Mice Causes Intrauterine Growth Restriction and Alters Postnatal Cardiac Growth, Morphology, and Function

Cited by 26 publications

References 53 publications

Fetal cardiac rhabdomyomas treated with maternal sirolimus

Fetal cardiac rhabdomyomas treated with maternal sirolimus

Choline Inhibits Ischemia-Reperfusion-Induced Cardiomyocyte Autophagy in Rat Myocardium by Activating Akt/mTOR Signaling

Role of the mTOR signalling pathway in salivary gland development

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