Date of Award
11-2024
Document Type
Dissertation
Degree Name
Doctor of Philosophy (PhD)
Program
Biomedical Sciences
Track
Molecular and Translational Physiology
Research Advisor
Stephen E. Alway, PhD
Committee
James Carson Ph.; Junaith Mohamed PhD; Helena Parfenova PhD; Webb Smith PhD; Zhongjie Sun MD,PhD
Keywords
Exosomes; Extracellular Vesicles; Type 2 Diabetes; Metabolism; Exercise; Adaptation; Glucose; Insulin Sensitivity
Abstract
Current evidence from the literature suggests a role for circulating extracellular vesicles (EVs) in the pathogenesis of multiple diseases as well as a potential therapeutic role via delivery of vesicular cargo. Type 2 Diabetes is among the most prevalent and costly metabolic diseases in the world. Lifestyle intervention including exercise can cause Type 2 Diabetes to enter effective remission but remain ineffective due to poor adherence. Exercise stimulates the release of EVs from the skeletal muscle (and other tissues), and these vesicles are thought to confer a portion of the metabolic benefits of exercise. However, the direct effects of EV’s to regulate muscle metabolic disruption or how exercise-modified EVs regulate skeletal muscle gene signaling in Type 2 Diabetes is not well understood. The purpose of this project was to study EVs on skeletal muscle cells to identify the mechanisms through which circulating extracellular vesicles contribute to the phenotype of Type 2 Diabetes; and to evaluate the effects of exercise associated EVs in a mouse model of Type 2 Diabetes. We addressed this problem in part via a novel model for investigation of EVs. In our model, we utilized exosome free cell culture media to replace depleted exosomes with those from control or diabetic mice. Using this approach, we demonstrate that exosomes from diabetic mice significantly impair insulin stimulated uptake of 2-NBDG (a fluorescent glucose analog). We also report that this occurs without alteration in phosphorylation of AKT. We also observed marked deposition on neutral lipids in myotubes after exposure with no changes in expression of a subset of genes important for lipid synthesis or import. Next, we employed 3’ end RNA seq to identify differentially regulated genes in response to exosomes associated with both aerobic exercise and type 2 diabetes. We found that exosomes associated with aerobic exercise robustly downregulated the expression of MAP2K6 whereas diabetes associated exosomes upregulated the expression of PRKD1. This is important because both genes may uniquely contribute to insulin sensitivity and overall muscle health. Finally, we investigated the therapeutic utility of intravenous administration of exercise associated exosomes for diabetic mice. While the exercise exosomes improved run to fatigue time and decreased intraperitoneal glucose tolerance test area under the curve, there was no improvement in muscle mass or force production, HOMA-IR index, or hemoglobin A1C in diabetic animals. We therefore must conclude that aerobic exercise associated exosomes confer functional and metabolic benefits associated with exercise but are ineffective as a therapeutic for type 2 diabetes.
ORCID
https://orcid.org/0009-0001-2529-4880
DOI
10.21007/aetd.cghs.2024.0014
Recommended Citation
Pitzer, Christopher R. (https://orcid.org/0009-0001-2529-4880), "Circulating Exosomes Alter Skeletal Muscle Gene Expression to Impair Insulin Sensitivity in Type 2 Diabetes and Mediate Adaptive Response to Exercise in Healthy Mice" (2024). Alternative Theses and Dissertations (AETDs). Paper 14. http://dx.doi.org/10.21007/aetd.cghs.2024.0014.
https://dc.uthsc.edu/aetd/14
Included in
Endocrine System Diseases Commons, Medical Molecular Biology Commons, Medical Physiology Commons, Nutritional and Metabolic Diseases Commons