Early life growth-restriction increases the risk for chronic disease development in adulthood and reduces levels of adulthood physical activity engagement. Furthermore, recent evidence suggests that growth-restricted mice may not respond positively to physical activity engagement. The adverse cardiovascular responses have not been observed in humans nor have physical activity interventions targeted critical windows of development to counteract negative effects of growth-restriction. The objective of this dissertation was to determine the effectiveness of interventions implemented at different timepoints to improve health in the early life growth-restricted population. To accomplish this objective, we proposed the following aims: 1) to determine the effectiveness of adulthood physical activity engagement in growth-restricted humans through the Framingham Offspring Cohort dataset, 2) to determine the effect of exercise during pregnancy on promoting physical activity in growth-restricted mouse pups, and 3) to determine the effect of an early life motor skill training intervention on promoting adulthood physical activity in growth-restricted mouse pups.℗ ℗ To accomplish the first aim, access to the Framingham Offspring Cohort was obtained. Physical activity parameters, chronic disease information, and birthweight information were required for inclusion in the study. We demonstrated that low birthweight (LBW) individuals had elevated markers of chronic disease risk (blood triglycerides and glucose concentrations) at both exam visits. Furthermore, LBW females trended (P=0.06) to spend more time sedentary at exam 5, while LBW men spent significantly more time sedentary at exam 9 (P=0.03). The likelihood of being treated for chronic disease was not different between low and normal birthweight participants at either timepoint. Biomarkers of chronic disease, however, remained elevated in low birthweight participants when total physical activity was included in the analysis as a covariate. The results demonstrate LBW humans display greater levels of physical inactivity and may not experience positive adaptations to adulthood physical activity. Interventions should therefore be implemented prior to adulthood that target improving physical activity behavior.℗ In the second study, dams engaged in a submaximal treadmill running protocol throughout gestation. Offspring were then growth-restricted in early life to measure the protective effects of maternal physical activity throughout gestation on offspring physical activity. First, mouse dams were assigned to a low-protein diet or a fully nourishing control diet two weeks prior to breeding, then assigned to a submaximal treadmill℗ running protocol throughout gestation. Following birth, a validated cross-fostering nutritive model was implemented to cause early life growth-restriction in half the study sample. Experimental pups were then weaned and given access to a free-moving running wheel throughout adulthood to assess physical activity engagement. At day 70, mice were euthanized and their nucleus accumbens excised for measurement of the dopamine receptor 1 (Drd1). In this study, mice born to exercised dams were significantly smaller in early life compared to pups born to sedentary dams but did not differ in weight throughout adulthood. Pups born to exercised dams completed more wheel revolutions during the light cycle in conjunction with a greater time spent running. We concluded that maternal exercise throughout gestation can improve offspring physical activity engagement by increasing the time spent engaging in physical activity, even in the growth-restricted population, without exacerbating the negative effects of early life growth-restriction.In the third study, mouse pups were growth-restricted in early life following the same validated cross-fostering nutritive model as the second study. Experimental pups in study 3 were also tested for development of specific mouse motor milestones. At day 10, pups were assigned to 2 groups: one group received an early life motor skill intervention from days 10-21 of the pup's life, while the other group remained a sedentary control. All pups were then weaned at 21 days of age and given access to a free moving running wheel at 45 days of age to assess physical activity engagement. At day 70, mice were euthanized and the abundance of Drd1 in the nucleus accumbens and abundance of Annexin A6 and Calsequestrin 1in the soleus were measured. We found that PGR mice had impaired motor skills throughout early development compared to control mice. The early life motor skill intervention did not alter any wheel running behavior, and control mice did run more revolutions than PGR mice during the week 2 dark cycle. While early life growth-restriction reduced motor skill attainment throughout early life, the early life motor skill intervention was not sufficient to elicit changes to adulthood behavior. More intense interventions that specifically target skeletal muscle may be necessary to counteract the detrimental effects of early life growth-restriction.The results of this dissertation highlight the importance of implementing interventions prior to adulthood in the growth-restricted population. Furthermore, the two early life behavioral interventions utilized in this dissertation elicited only slight improvements in physical activity engagement, and thus more intense interventions may be needed to elicit greater changes to adulthood physical activity.
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