Date of Award

8-16-2024

Document Type

Open Access Thesis

Department

Biomedical Science

First Advisor

Angela Murphy

Abstract

By the year 2030, almost 50% of adults in the United States are expected to be obese. Obesity has been shown to increase the risk of several chronic metabolic diseases, several cancers, and is associated with impaired skeletal muscle function and metabolism. Despite this, little it is known about the role of altered muscle lipid homeostasis, lipid droplet dynamics, and lipid droplet-mitochondrial interactions in contributing to muscle dysfunction in obesity. Therefore, we sought to investigate the impact of high-fat diet induced obesity on overall skeletal muscle lipid deposition, intramyocellular lipid droplet content and morphology, and lipid droplet-mitochondrial contact. Male C57/BL6 mice (n=20) were divided into two groups: one group received LLC cell implants (106 cells) in the right flank, while the other group underwent sham surgery. After 25 days, skeletal muscle samples were collected transmission electron microscopy (TEM; soleus), oil red o/lipid staining (tibialis anterior), and protein analysis (gastrocnemius). Statistical analysis was performed using a Student’s T-test with an alpha level of 0.05. Protein analyses revealed dysregulation in key metabolic regulatory proteins (Atrogin-1, Adiponectin, PLIN-2, total and phosphorylated (t and p) AKT Thr308/Ser473, MURF1) accompanied by increases in oil red o staining in obese compared to lean mice. This was further supported by obese mice exhibiting a greater number of intramyocellular lipid droplets. Furthermore, morphological examination of lipid droplets showed alterations in shape parameters (e.g., roundness, circularity, aspect ratio), along with reduced contact between lipid droplets and mitochondria. Collectively, these findings suggest that obesity-induced skeletal muscle dysfunction may be driven, at least in part, due to changes in lipid droplet-mitochondria interactions resulting in excess accumulation of lipids and altered lipid droplet morphology.

Rights

© 2024, Alexander Huss

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