Identifier

etd-06292012-211739

Degree

Doctor of Philosophy (PhD)

Department

Renewable Natural Resources

Document Type

Dissertation

Abstract

Insulin resistance in type 2 diabetes is associated with impaired glucose and protein metabolism in skeletal muscle. The impaired insulin signaling in skeletal muscle affects muscle mass by tilting the balance between skeletal muscle protein synthesis and degradation toward degradation, a process that is primarily regulated by the ubiquitin-proteasome system. Studies have shown that an extensively characterized ethanol extract of Artemisia dracunculus L (Russian Tarragon), termed PMI 5011, enhances insulin signaling in human primary skeletal muscle cells and in a rodent model of insulin resistance. The aim of this project is to determine if the effect of PMI 5011 on insulin signaling extends to regulation of ubiquitin-proteasome activity in skeletal muscle. To evaluate the effect of PMI 5011 on the ubiquitin-proteasome system, we used two in vitro models of insulin resistance in C2C12 myotubes and the KKAy mouse model of insulin resistance in vivo. Our studies show that PMI 5011 enhances the inhibitory effect of insulin on proteasome activity and ubiquitylation in skeletal muscle in vitro and in vivo. In addition, PMI 5011 inhibits non-proteasomal protein degradation in vivo, indicating that PMI 5011 is a potent inhibitor of skeletal muscle protein degradation. PMI 5011 also regulates the expression of Atrogin-1 and MuRF-1, muscle-specific ubiquitin ligases that are required for ubiquitin-dependent protein degradation in skeletal muscle. Both Atrogin-1 and MuRF-1 gene and protein expression is elevated with impaired insulin signaling and our studies show that PMI 5011 reduces the expression of these ligases while enhancing Akt phosphorylation. In summary, these studies demonstrate that PMI 5011 regulates the ubiquitin-proteasome in insulin resistant states in vitro and in vivo. PMI 5011 may therefore be a therapeutic target for enhancing insulin sensitivity leading to conservation of muscle mass in type 2 diabetes.

Date

2012

Document Availability at the Time of Submission

Release the entire work immediately for access worldwide.

Committee Chair

Liu, Zhijun

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