Effects of maternal exercise on infant mesenchymal stem cell metabolism and adiposity

Abstract

The prevalence of pediatric obesity is escalating worldwide. The programming of obesity begins in utero and is dependent on the environmental exposures experienced during intrauterine and early postnatal life. Maternal obesity potentiates the development and transmission of obesity to progeny, subsequently increasing their risk for the development of metabolic disorders later in life. To date, maternal obesity has been associated with fetal overgrowth and infant adiposity; however, the underlying mechanisms behind this remain confined to animal models. Infant mesenchymal stem cells (MSCs) give rise to infant tissues (e.g., skeletal muscle), remain involved in mature tissue repair and maintenance, and align with the metabolic phenotype of the offspring donor. Previous research has linked lower infant MSC mitochondrial oxidative capacity with increased infant adiposity. These findings showcase the responsiveness of infant mitochondria to the intrauterine environment and implicate energy metabolism in intergenerational health transmission. Furthermore, infant adiposity has been directly correlated with the degree of fetal insulin resistance. Exercise in non-gravid populations has been associated with improvements in mitochondrial functional capacity and insulin action. Furthermore, maternal exercise has been associated with decreased infant adiposity; however, mechanistic insight behind these adaptations remain largely unknown in humans. To address this gap, we recruited healthy females <16 weeks' gestation, and randomized them to supervised moderate-intensity exercise (aerobic, resistance, or combination) or a control group, for the duration of their pregnancy. To investigate the impact of maternal exercise on infant metabolism we collected infant MSCs at birth. To address the effects of maternal exercise on infant adiposity, we followed up with infants at 1- and 6-months of age to assess their body composition. In aim one of this dissertation, we show that maternal exercise, irrespective of exercise mode, is associated with higher infant MSC mitochondrial respiration, fat oxidation, insulin action, and expression and activation of energy sensing and redox-sensitive proteins. These adaptations were seemingly independent of mitochondrial content, oxidative phosphorylation, and electron transport system capacity changes. Furthermore, this phenotype was associated with lower infant adiposity at 1-month of age, independent of changes in lean body mass. Finally, we showcase the association between maternal gestational exercise volume, but not pre-pregnancy aerobic capacity, with multiple aspects of MSC metabolism and infant adiposity. In aim two of the dissertation, we show that maternal exercise is associated with an increase in infant myogenic-differentiated MSCs, a model of infant skeletal muscle tissue, insulin action. Furthermore, we showcase that an increase in insulin action in MSC undergoing myogenesis is associated with higher MSC fat oxidation and glucose partitioning towards complete oxidation rather than non-oxidized glycolysis, and lower infant adiposity in the first 6 months of life. Collectively, these data showcase the array of metabolic adaptations that maternal exercise has on offspring MSC metabolism and adiposity. These findings support maternal exercise as a safe non-pharmacological intervention to decrease the transgenerational propagation of metabolic disease.