Honors College Thesis
 

Short-Term Lipid Overload in Skeletal Muscle Induces Mild Mitochondrial Membrane Depolarization as a Stimulus for Autophagy Activation

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https://ir.library.oregonstate.edu/concern/honors_college_theses/s4655p91t

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  • Type 2 Diabetes Mellitus is a chronic metabolic condition that impairs insulin stimulated glucose absorption in skeletal muscle, a characteristic phenomenon denoted as insulin resistance. Lipid overload of the mitochondria is linked to the development of insulin resistance and the progression of Type 2 Diabetes. As lipids accumulate there is an increased demand on mitochondrial metabolism, inducing oxidative stress and promotion of reactive oxygen species formation within the mitochondria, generating a source of damage. To maintain homeostasis during lipid induced oxidative stress, mitochondrial remodeling through targeted degradation of damaged mitochondria via autophagy contributes to the adaptive response. The purpose of this study was to investigate the short-term effects of lipid overload on mitochondrial regulation and remodeling in skeletal muscle, and to identify potential lipid stimulated mitochondrial membrane depolarization due to reactive oxygen species formation as a stimulus for autophagy. C2C12 mouse myoblasts were cultured and treated with palmitate for 4, 8, and 24 hours to identify initial mitochondrial adaptations to lipid overload. Mitochondrial protein markers of autophagy were quantified to identify differences in protein abundance and autophagy signaling. In cultured myotubes, palmitate treatment induced an increased abundance of upstream autophagy activation protein markers but displayed impaired autophagosome localization. Lipid overload also stimulated a mild decrease in mitochondrial membrane potential, suggestive of increased reactive oxygen species production as a signal for mitochondrial adaptation. We conclude that short-term lipid overload in skeletal muscle induces autophagy activation caused by mitochondrial membrane depolarization in response to lipid overload.
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