Early life growth-restriction is a significant global issue, with over 161 million children experiencing growth-restriction under the age of 5 years. Undernutrition induced growth restriction during postnatal life (PNGR) is characterized by permanent stunting of growth and is associated with increased risk of developing cardiometabolic disease in adulthood. Additionally, PNGR significantly reduces exercise capacity in adulthood, further increasing the risk for chronic disease development. Exercise is beneficial in preventing and treating cardiometabolic disease, however, evidence characterizing the metabolic effects of exercise in the PNGR population is limited. Furthermore, it has become increasingly evident from recent literature that metabolism is impacted not only by host biochemical pathways but also that from the gut microbiome. Human metabolism should be studied from a holistic approach including impacts from microbial residents of the gut, human tissues, and the interplay between both entities. There is also evidence that the gut microbiome plays a role in exercise adaptations, both of which are altered as a response to PNGR as previously shown in mice. Recent studies have investigated the effects of high-intensity interval training (HIIT) in comparison to more commonly tested moderate-intensity continuous exercise protocols which resulted in more pronounced health benefits and in a shorter timeframe, especially in individuals with chronic disease. Until now, however, HIIT has yet to be tested in the PNGR population, as well as its effects on the microbiome and metabolome. The three objectives of this dissertation were to 1) determine the effect of a HIIT intervention on maximal exercise capacity (Wmax) in adult PNGR mice as compared to controls (CON), 2) to determine the effects of HIIT on the microbial compositions in PNGR and CON, and 3) to determine the effects of HIIT on the gut and serum metabolome in PNGR and CON. For the first objective, exercise capacity (Wmax) was assessed via maximal treadmill tests performed at baseline, after one week of training, and post-intervention. Wmax data analyzed via repeated measures ANOVA between baseline and post-intervention revealed improvements in all treatment groups. HIIT resulted in showed greater positive improvements in CON compared to PNGR and in males as compared to their respective female counterparts. HIIT was successful in improving Wmax in PNGR, which has yet to be shown in previous studies utilizing this mouse model. Future work is encouraged to further examine physiological aspects allowing adaptation to HIIT in areas such as skeletal muscle or cardiovascular differentiation with training in PNGR compared to CON. To accomplish the second objective, fecal samples were used to profile the gut microbiome. It was hypothesized that HIIT in CON and PNGR would increase microbial diversity as well as enrichment of unique taxa compared to their SED counterparts. Majority of the microbial differences, aside from a few genre and species differences, were not significant between treatment groups. Two microbes Christenellacae g.s. and Clostridiacae g.s. were altered in response to HIIT, although their specific roles in exercise capacity or adaptation are currently not clear. To accomplish the third objective, fecal and serum samples collected post-intervention were processed for untargeted metabolomics. The effects of HIIT on host metabolism was evidently differential in PNGR compared to CON, with alternate patterns of heme, glutathione and acylcarnitine abundances post-intervention. Despite exposure to 4-weeks of HIIT, PNGR retained downregulated essential amino acids, acylcarnitines, glutathione and heme, all of which are potentially important components in the process of exercise adaptations. To summarize, PNGR leads to reduced exercise capacity which improves with HIIT, although the metabolome remains significantly altered compared to CON. By accomplishing the objectives of this dissertation, a more comprehensive profile of the metabolic baseline as well as responses to HIIT were characterized. It is encouraged that future studies further examine and compare the cardiovascular, skeletal muscle and mitochondrial activities in response to HIIT to determine where the alterations in metabolome derive from in PNGR.
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