Novel roles of mechanistic target of rapamycin signaling in regulating fetal growth†

Abstract Mechanistic target of rapamycin (mTOR) signaling functions as a central regulator of cellular metabolism, growth, and survival in response to hormones, growth factors, nutrients, energy, and stress signals. Mechanistic TOR is therefore critical for the growth of most fetal organs, and global mTOR deletion is embryonic lethal. This review discusses emerging evidence suggesting that mTOR signaling also has a role as a critical hub in the overall homeostatic control of fetal growth, adjusting the fetal growth trajectory according to the ability of the maternal supply line to support fetal growth. In the fetus, liver mTOR governs the secretion and phosphorylation of insulin-like growth factor binding protein 1 (IGFBP-1) thereby controlling the bioavailability of insulin-like growth factors (IGF-I and IGF-II), which function as important growth hormones during fetal life. In the placenta, mTOR responds to a large number of growth-related signals, including amino acids, glucose, oxygen, folate, and growth factors, to regulate trophoblast mitochondrial respiration, nutrient transport, and protein synthesis, thereby influencing fetal growth. In the maternal compartment, mTOR is an integral part of a decidual nutrient sensor which links oxygen and nutrient availability to the phosphorylation of IGFBP-1 with preferential effects on the bioavailability of IGF-I in the maternal–fetal interface and in the maternal circulation. These new roles of mTOR signaling in the regulation fetal growth will help us better understand the molecular underpinnings of abnormal fetal growth, such as intrauterine growth restriction and fetal overgrowth, and may represent novel avenues for diagnostics and intervention in important pregnancy complications.

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Mechanistic target of rapamycin (mTOR) signaling genes in decapod crustaceans: Cloning and tissue expression of mTOR, Akt, Rheb, and p70 S6 kinase in the green crab, Carcinus maenas, and blackback land crab, Gecarcinus lateralis

Comparative Biochemistry and Physiology Part A Molecular & Integrative Physiology ◽

10.1016/j.cbpa.2013.11.008 ◽

2014 ◽

Vol 168 ◽

pp. 25-39 ◽

Cited By ~ 23

Author(s):

Ali M. Abuhagr ◽

Kyle S. MacLea ◽

Ernest S. Chang ◽

Donald L. Mykles

Keyword(s):

Carcinus Maenas ◽

Tissue Expression ◽

Mtor Signaling ◽

Green Crab ◽

Target Of Rapamycin ◽

Decapod Crustaceans ◽

S6 Kinase ◽

P70 S6 Kinase ◽

Land Crab ◽

Mechanistic Target Of Rapamycin

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The effect of intermittent umbilical cord occlusion on insulin-like growth factors and their binding proteins in preterm and near-term ovine fetuses

Journal of Endocrinology ◽

10.1677/joe.0.1660565 ◽

2000 ◽

Vol 166 (3) ◽

pp. 565-577 ◽

Cited By ~ 14

Author(s):

LR Green ◽

Y Kawagoe ◽

DJ Hill ◽

BS Richardson ◽

VK Han

Keyword(s):

Skeletal Muscle ◽

Growth Factors ◽

Umbilical Cord ◽

Fetal Growth ◽

Binding Proteins ◽

Negative Impact ◽

Mrna Levels ◽

Igf I ◽

Near Term ◽

Insulin Like Growth Factors

Intermittent umbilical cord compression with resultant fetal hypoxia can have a negative impact on fetal growth and development. Insulin-like growth factors (IGFs) and their binding proteins (IGFBPs) are the most important regulators of fetal growth. In preterm (107-108 days of gestation) and near-term (128-131 days of gestation) ovine fetuses, we have determined the effect of intermittent umbilical cord occlusion (UCO) over a period of 4 days on the profile and expression of IGFs and IGFBPs. In experimental group animals (preterm n=7; near term n=7) UCOs were carried out by complete inflation of an occluder cuff (duration 90 s) every 30 min for 3-5 h each day, while control fetuses (preterm n=7; near term n=7) received no UCOs. Ewes were euthanized at the end of day 4, and fetal heart, lung, kidney, liver, skeletal muscle and placenta were collected. During UCOs, PO(2! ) fell (by approximately 13 mmHg), pH fell (by approximately 0.05) and PCO(2) increased (by approximately 7 mmHg), and changed to a similar extent in both preterm and near-term groups. In both preterm and near-term groups, there was no difference in fetal body or organ weight between UCO and control fetuses. No significant changes were observed in plasma IGF-I and -II concentrations or IGFBP-1, -2, -3 or -4 levels throughout the 4-day study at either gestational age. In the preterm group UCO fetuses, IGF-II mRNA (1.2-6.0 kb) levels were lower in fetal lung (33%, P<0.05), heart (54%, P<0.01) and skeletal muscle (29%, P<0.05), but there were no differences in IGF-I mRNA levels (7.3 kb); IGFBP-2 mRNA (1.5 kb) levels were lower in the right lobe of the liver (42%, P<0.05) and kidney (22%, P<0.01), but hig! her in the heart (72%, P<0.01), while IGFBP-4 (2.4 kb) levels were lower in skeletal muscle (21%, P<0.01). In the near-term group UCO fetuses, IGFBP-2 mRNA levels were greater in the placenta (39%, P<0.05). Thus, intermittent UCO as studied has a greater effect on the expression of genes encoding certain peptides of the fetal IGF system in selected tissues in preterm fetuses than that in near-term fetuses. Altered IGFBP-2 mRNA levels with reduced IGF-II mRNA levels in selected tissues may mediate changes in growth and/or differentiation that might become apparent if the length of the UCO study were extended.

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Mechanistic target of rapamycin (mTOR) signaling in status epilepticus

Epilepsy & Behavior ◽

10.1016/j.yebeh.2019.106550 ◽

2019 ◽

Vol 101 ◽

pp. 106550 ◽

Cited By ~ 4

Author(s):

Peter B. Crino

Keyword(s):

Status Epilepticus ◽

Mtor Signaling ◽

Target Of Rapamycin ◽

Mechanistic Target Of Rapamycin

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Circulating insulin-like growth factors-I and -II and substrates in fetal sheep following restriction of placental growth

Journal of Endocrinology ◽

10.1677/joe.0.1400005 ◽

1994 ◽

Vol 140 (1) ◽

pp. 5-13 ◽

Cited By ~ 77

Author(s):

J A Owens ◽

K L Kind ◽

F Carbone ◽

J S Robinson ◽

P C Owens

Keyword(s):

Growth Factors ◽

Blood Glucose ◽

Fetal Growth ◽

Fetal Liver ◽

Liver Weight ◽

Fetal Weight ◽

Fetal Sheep ◽

Arterial Blood ◽

Igf I ◽

Insulin Like Growth Factors

Abstract To determine the relationship between placental delivery of oxygen and glucose, circulating insulin-like growth factors (IGFs) and fetal growth, the effect of variable restriction of placental growth was determined in sheep in late gestation. Arterial blood was obtained via indwelling catheters at 120 and 127 days of gestation, prior to necropsy at 130 days to measure fetal and placental weights. Plasma was acidified and subjected to size-exclusion high-performance liquid chromatography at pH 2·8 to dissociate and separate IGFs from their binding proteins. The acid-dissociated IGF fraction was analysed by sensitive and highly specific radioligand assays for IGF-I and IGF-II, previously defined using ovine IGFs. Fetal weight and blood pO2 and glucose at 120 and 127 days of gestation correlated positively with placental weight. Plasma IGF-I was positively associated with fetal weight and fetal liver weight, and with blood pO2 and glucose at both ages. Plasma IGF-II levels also correlated positively with fetal weight, fetal liver weight and with blood glucose and pO2, but only at 127 days of gestation. In the most severely growth-retarded fetal sheep, blood glucose and pO2 and plasma IGF-I were significantly reduced when compared with normal fetuses at 120 days. All decreased further by 127 days of gestation as did plasma IGF-II in severely growth-retarded fetal sheep compared with normal fetuses. These observations are consistent with the hypothesis that both IGF-I and IGF-II are chronically regulated by oxygen and nutrition in utero and mediate part of the influence of placental supply of substrate over fetal growth. Journal of Endocrinology (1994) 140, 5–13

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Impaired trophoblast mitochondrial function following maternal nutrient restriction (MNR) in the baboon is alleviated by activation of mechanistic Target of Rapamycin (mTOR) signaling

Placenta ◽

10.1016/j.placenta.2016.06.105 ◽

2016 ◽

Vol 45 ◽

pp. 91

Author(s):

Fredrick Joseph Rosario ◽

Cun Li ◽

Leslie Myatt ◽

Theresa Powell ◽

Peter W. Nathanielsz ◽

...

Keyword(s):

Mitochondrial Function ◽

Mtor Signaling ◽

Target Of Rapamycin ◽

Nutrient Restriction ◽

Mechanistic Target Of Rapamycin

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Maternal growth factor regulation of human placental development and fetal growth

Journal of Endocrinology ◽

10.1677/joe-10-0174 ◽

2010 ◽

Vol 207 (1) ◽

pp. 1-16 ◽

Cited By ~ 71

Author(s):

Karen Forbes ◽

Melissa Westwood

Keyword(s):

Growth Factors ◽

Growth Factor ◽

Fetal Growth ◽

Mechanism Of Action ◽

Normal Development ◽

Receptor Interaction ◽

Placental Development ◽

Maternal Circulation ◽

Successful Pregnancy ◽

And Function

Normal development and function of the placenta is critical to achieving a successful pregnancy, as normal fetal growth depends directly on the transfer of nutrients from mother to fetus via this organ. Recently, it has become apparent from both animal and human studies that growth factors within the maternal circulation, for example the IGFs, are important regulators of placental development and function. Although these factors act via distinct receptors to exert their effects, the downstream molecules activated upon ligand/receptor interaction are common to many growth factors. The expression of numerous signaling molecules is altered in the placentas from pregnancies affected by the fetal growth complications, fetal growth restriction, and macrosomia. Thus, targeting these molecules may lead to more effective treatments for complications of pregnancy associated with altered placental development. Here, we review the maternal growth factors required for placental development and discuss their mechanism of action.

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Role of mTor signaling for tubular function and disease

Physiology ◽

10.1152/physiol.00021.2021 ◽

2021 ◽

Author(s):

Florian Grahammer ◽

Tobias B Huber ◽

Ferruh Artunc

Keyword(s):

Diabetic Nephropathy ◽

Actin Cytoskeleton ◽

Mtor Signaling ◽

Tubular Function ◽

Target Of Rapamycin ◽

Multiprotein Complexes ◽

Mechanistic Target Of Rapamycin ◽

Transport Regulation ◽

Disease Entities

The mechanistic target of rapamycin (mTOR) forms two distinct intracellular multiprotein complexes that control a multitude of intracellular processes linked to metabolism, proliferation, actin cytoskeleton and survival. Recent studies have identified the importance of these complexes for transport regulation of ions and nutrients along the entire nephron. First reports could link altered activity of these complexes to certain disease entities i.e. diabetic nephropathy, AKI or hyperkalemia.

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The neglected role of insulin-like growth factors in the maternal circulation regulating fetal growth

The Journal of Physiology ◽

10.1113/jphysiol.2010.198622 ◽

2010 ◽

Vol 589 (1) ◽

pp. 7-20 ◽

Cited By ~ 51

Author(s):

A. N. Sferruzzi-Perri ◽

J. A. Owens ◽

K. G. Pringle ◽

C. T. Roberts

Keyword(s):

Growth Factors ◽

Fetal Growth ◽

Maternal Circulation ◽

Insulin Like Growth Factors

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Mechanistic target of rapamycin signaling in mouse models of accelerated aging

The Journals of Gerontology Series A ◽

10.1093/gerona/glz059 ◽

2019 ◽

Vol 75 (1) ◽

pp. 64-72 ◽

Cited By ~ 4

Author(s):

Jin Young Lee ◽

Brian K Kennedy ◽

Chen-Yu Liao

Keyword(s):

Mouse Models ◽

Accelerated Aging ◽

Nutrient Sensing ◽

Mtor Signaling ◽

Human Diseases ◽

Target Of Rapamycin ◽

Cellular Processes ◽

Positive Effects ◽

Mechanistic Target Of Rapamycin ◽

Age Related

Abstract The mechanistic target of rapamycin (mTOR) is an essential nutrient-sensing kinase that integrates and regulates a number of fundamental cellular processes required for cell growth, cell motility, translation, metabolism, and autophagy. mTOR signaling has been implicated in the progression of many human diseases, and its dysregulation has been reported in several pathological processes, especially in age-related human diseases and mouse models of accelerated aging. In addition, many studies have demonstrated that the regulation of mTOR activity has a beneficial effect on longevity in several mouse models of aging. However, not all mouse models of accelerated aging show positive effects on aging-associated phenotypes in response to targeting mTOR signaling. Here, we review the effects of interventions that modulate mTOR signaling on aging-related phenotypes in different mouse models of accelerated aging and discuss their implications with respect to aging and aging-related disorders.

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