Nicholas BroskeyKrassovskaia, Polina2024-08-292024-07July 2024July 2024http://hdl.handle.net/10342/13671Metabolic disease continues to be a worldwide problem that affects all ages, sexes, and socioeconomic statuses. The development of metabolic disease is multifactorial with both genetic and environmental components. Because of this, interest has grown in the early identification of individuals susceptible towards the development of metabolic disease. Metabolic flexibility has gained standing as a metric of metabolic health and can be defined as the ability to appropriately adapt substrate utilization in response to substrate availability. Skeletal muscle (SkM) is a regulator of metabolic flexibility as it is the primary tissue responsible for post-prandial substrate handling, and metabolic inflexibility can be seen in the SkM of individuals with metabolic disease. As Western style diets are proportionally heavy in fats and implicated in the development of obesity, metabolic flexibility with lipids is of particular interest. High-fat diets (HFDs) are a common and successful approach for distinguishing differences in metabolic flexibility with lipids across populations. Some evidence exists for metabolic inflexibility in healthy, lean individuals, which suggests metabolic flexibility may be an innate component of SkM. Studies of individuals with overweight allow insight into the intrinsic characteristics of SkM that promote the development of metabolic disease, yet this population remains largely understudied. The current study aimed to assess metabolic flexibility in a population of healthy individuals with overweight with a 3-day HFD. In chapter 2, we show that the participants studied are sedentary, have overweight, and do not display evidence of dysglycemia or dyslipidemia. Participants did not differ in dietary habits before or during the diet. Metabolic flexibility was calculated as the change in SkM homogenate palmitate oxidation with the high-fat diet. Metabolically flexible individuals show almost a two-fold increase in palmitate oxidation with the diet, while inflexible individuals decrease oxidation by about one-third of pre-diet rates, and this occurs without any changes to pyruvate oxidation. Metabolic flexibility was not associated with skeletal muscle fiber type. The change in the respiratory quotient during a hyperinsulinemic-euglycemic clamp is a classical approach towards assessing metabolic flexibility; we found that this was not associated with metabolic flexibility when measured as the change in palmitate oxidation in homogenates with the diet. Additionally, flexible and inflexible participants did not differ in mitochondrial function. Taken together, this indicates that metabolic flexibility is an innate component of SkM and can be seen prior to any clinical evidence of metabolic disruption, and metabolic flexibility is not associated with either muscle fiber type or mitochondrial function. In chapter 3, we utilized primary human skeletal muscle stem cells (HSkMCs) of the same cohort of participants studied in chapter 2. We show that a 3-day HFD does not result in changes in HSkMC metabolism measured by substrate oxidation, glycogen synthesis, and protein content of mitochondrial markers and PGC1a. Cells were additionally incubated with a lipid cocktail for 24 hours, which has been shown to help distinguish differences in metabolic flexibility in HSkMCs. Even with lipid treatment, no effect of the HFD was seen. Although participants were stratified based off the change in palmitate oxidation seen in SkM homogenates, a main finding was that HSkMCs of flexible individuals show enhanced glucose metabolism seen as higher glucose oxidation efficiency. Interestingly, measures of HSkMC lipid metabolism did not associate with similar measures of homogenate lipid metabolism. Together, these data provide novel findings demonstrating that metabolic inflexibility is present in SkM prior to detection at the whole-body level and occurs without any clinical markers of metabolic disturbance.application/pdfEnglishHealth Sciences, KinesiologyHealth Sciences, GeneralDoctoral Dissertation2024-08-27