Effects of maternal exercise on infant mesenchymal stem cell mitochondrial function, insulin action, and body composition in infancy.

Maternal exercise (ME) has been established as a useful non-pharmacological intervention to improve infant metabolic health; however, mechanistic insight behind these adaptations remains mostly confined to animal models. Infant mesenchymal stem cells (MSCs) give rise to infant tissues (e.g., skeletal muscle), and remain involved in mature tissue maintenance. Importantly, these cells maintain metabolic characteristics of an offspring donor and provide a model for the investigation of mechanisms behind infant metabolic health improvements. We used undifferentiated MSC to investigate if ME affects infant MSC mitochondrial function and insulin action, and if these adaptations are associated with lower infant adiposity. We found that infants from exercising mothers have improvements in MSC insulin signaling related to higher MSC respiration and fat oxidation, and expression and activation of energy-sensing and redox-sensitive proteins. Further, we found that infants exposed to exercise in utero were leaner at 1 month of age, with a significant inverse correlation between infant MSC respiration and infant adiposity at 6 months of age. These data suggest that infants from exercising mothers are relatively leaner, and this is associated with higher infant MSC mitochondrial respiration, fat use, and insulin action.

Differences in substrate metabolism between African American and Caucasian infants: evidence from mesenchymal stem cells.

Type 2 diabetes is more prevalent in African American (AA) than Caucasian (C) adults. Furthermore, differential substrate utilization has been observed between AA and C adults, but data regarding metabolic differences between races at birth remains scarce. The purpose of the present study was to determine if there are racial differences in substrate metabolism evident at birth using a mesenchymal stem cells (MSCs) collected from offspring umbilical cords. Using radio-labeled tracers, MSCs from offspring of AA and C mothers were tested for glucose and fatty acid metabolism in the undifferentiated state and while undergoing myogenesis in vitro. Undifferentiated MSCs from AA exhibited greater partitioning of glucose toward nonoxidized glucose metabolites. In the myogenic state, AA displayed higher glucose oxidation, but similar fatty acid oxidation rates. In the presence of both glucose and palmitate, but not palmitate only, AA exhibit a higher rate of incomplete fatty acid oxidation evident by a greater production of acid-soluble metabolites. Myogenic differentiation of MSCs elicits an increase in glucose oxidation in AA, but not in C. Together, these data suggest that metabolic differences between AA and C races exist at birth.NEW & NOTEWORTHY African Americans, when compared with Caucasians, display greater insulin resistance in skeletal muscle. Differences in substrate utilization have been proposed as a factor for this health disparity; however, it remains unknown how early these differences manifest. Using infant umbilical cord-derived mesenchymal stem cells, we tested for in vitro glucose and fatty acid oxidation differences. Myogenically differentiated MSCs from African American offspring display higher rates of glucose oxidation and incomplete fatty acid oxidation.

Intrinsic adaptations in OXPHOS power output and reduced tumorigenicity characterize doxorubicin resistant ovarian cancer cells.

Although the development of chemoresistance is multifactorial, active chemotherapeutic efflux driven by upregulations in ATP binding cassette (ABC) transporters are commonplace. Chemotherapeutic efflux pumps, like ABCB1, couple drug efflux to ATP hydrolysis and thus potentially elevate cellular demand for ATP resynthesis. Elevations in both mitochondrial content and cellular respiration are common phenotypes accompanying many models of cancer cell chemoresistance, including those dependent on ABCB1. The present study set out to characterize potential mitochondrial remodeling commensurate with ABCB1-dependent chemoresistance, as well as investigate the impact of ABCB1 activity on mitochondrial respiratory kinetics. To do this, comprehensive bioenergetic phenotyping was performed across ABCB1-dependent chemoresistant cell models and compared to chemosensitive controls. In doxorubicin (DOX) resistant ovarian cancer cells, the combination of both increased mitochondrial content and enhanced respiratory complex I (CI) boosted intrinsic oxidative phosphorylation (OXPHOS) power output. With respect to ABCB1, acute ABCB1 inhibition partially normalized intact basal mitochondrial respiration between chemosensitive and chemoresistant cells, suggesting that active ABCB1 contributes to mitochondrial remodeling in favor of enhanced OXPHOS. Interestingly, while enhanced OXPHOS power output supported ABCB1 drug efflux when DOX was present, in the absence of chemotherapeutic stress, enhanced OXPHOS power output was associated with reduced tumorigenicity.

Infant Mesenchymal Stem Cell Insulin Action Is Associated With Maternal Plasma Free Fatty Acids, Independent of Obesity Status: The Healthy Start Study.

Preclinical rodent and nonhuman primate models investigating maternal obesity have highlighted the importance of the intrauterine environment in the development of insulin resistance in offspring; however, it remains unclear if these findings can be translated to humans. To investigate possible intrauterine effects in humans, we isolated mesenchymal stem cells (MSCs) from the umbilical cord tissue of infants born to mothers of normal weight or mothers with obesity. Insulin-stimulated glycogen storage was determined in MSCs undergoing myogenesis in vitro. There was no difference in insulin action based on maternal obesity. However, maternal free fatty acid (FFA) concentration, cord leptin, and intracellular triglyceride content were positively correlated with insulin action. Furthermore, MSCs from offspring born to mothers with elevated FFAs displayed elevated activation of the mTOR signaling pathway. Taken together, these data suggest that infants born to mothers with elevated lipid availability have greater insulin action in MSCs, which may indicate upregulation of growth and lipid storage pathways during periods of maternal overnutrition.

Influence of Maternal Exercise on Glucose and Lipid Metabolism in Offspring Stem Cells: ENHANCED by Mom.

CONTEXT: Recent preclinical data suggest exercise during pregnancy can improve the metabolic phenotype not only of the mother, but of the developing offspring as well. However, investigations in human offspring are lacking. OBJECTIVE: To characterize the effect of maternal aerobic exercise on the metabolic phenotype of the offspring's mesenchymal stem cells (MSCs). DESIGN: Randomized controlled trial. SETTING: Clinical research facility. PATIENTS: Healthy female adults between 18 and 35 years of age and ≤ 16 weeks' gestation. INTERVENTION: Mothers were randomized into 1 of 2 groups: aerobic exercise (AE, n = 10) or nonexercise control (CTRL, n = 10). The AE group completed 150 minutes of weekly moderate-intensity exercise, according to American College of Sports Medicine guidelines, during pregnancy, whereas controls attended stretching sessions. MAIN OUTCOME MEASURES: Following delivery, MSCs were isolated from the umbilical cord of the offspring and metabolic tracer and immunoblotting experiments were completed in the undifferentiated (D0) or myogenically differentiated (D21) state. RESULTS: AE-MSCs at D0 had an elevated fold-change over basal in insulin-stimulated glycogen synthesis and reduced nonoxidized glucose metabolite (NOGM) production (P ≤ 0.05). At D21, AE-MSCs had a significant elevation in glucose partitioning toward oxidation (oxidation/NOGM ratio) compared with CTRL (P ≤ 0.05). Immunoblot analysis revealed elevated complex I expression in the AE-MSCs at D21 (P ≤ 0.05). Basal and palmitate-stimulated lipid metabolism was similar between groups at D0 and D21. CONCLUSIONS: These data provide evidence of a programmed metabolic phenotype in human offspring with maternal AE during pregnancy.

The impact of advanced maternal age on pregnancy and offspring health: A mechanistic role for placental angiogenic growth mediators.

The birth rates among women of advanced maternal age (AMA) have risen over the last two decades; yet, pregnancies with AMA are considered high-risk and are associated with a significant increase in pregnancy complications. Although the mechanisms leading to pregnancy complications in women with AMA are not fully understood, it has been well established in the literature that offspring exposed to unfavorable environmental conditions in utero, such as gestational diabetes, preeclampsia, and/or intrauterine growth restriction during the early stages of development are subject to long-term health consequences. Additionally, angiogenic growth mediators, which drive vascular development of the placenta, are imbalanced in pregnancies with AMA. These same imbalances also occur in pregnancies complicated by preeclampsia, gestational diabetes, and obesity. This review discusses the impact of AMA on pregnancy and offspring health, and the potential mechanistic role of placental angiogenic growth mediators in the development of pregnancy complications at AMA.