Year of Publication

2015

Degree Name

Doctor of Philosophy (PhD)

Document Type

Doctoral Dissertation

College

Medicine

Department

Physiology

First Advisor

Dr. Karyn A. Esser

Abstract

Metabolism is a critical physiological function that works to generate energy for cells, store substrates and maintain homoeostasis. Alterations in normal metabolism can have a severe effect on physiology, leading to metabolic disease. Skeletal muscle is a key metabolic tissue, taking up ~80% of postprandial glucose. Therefore it contributes considerably to glucose metabolism: glucose uptake, oxidation and homeostasis. To address the role of the skeletal muscle clock in insulin sensitivity and glucose tolerance, our lab generated an inducible skeletal muscle specific Bmal1-/- mouse (iMSBmal1-/-). 5 weeks post-recombination we observed impairment in both insulin- and AICAR-stimulated skeletal muscle glucose uptake. RT-PCR and western blot analysis demonstrated a significant decrease in mRNA expression and protein content of the skeletal muscle glucose transporter, Glut4. Glucose uptake may be affected by glucose utilization so we examined aspects of glycolysis in the skeletal muscle. Both mRNA expression and activity of rate limiting enzymes hexokinase 2 (Hk2) and phosphofructokinase 1 (Pfk1) were significantly reduced. Additionally, metabolomics illustrated a reduction in metabolites of the glycolytic pathway further supporting a decrease in glycolytic flux. These changes in skeletal muscle glucose metabolism led to altered overall body metabolic health. iMSBmal1-/- mice presented with glucose intolerance and non-fasting hyperglycemia. Furthermore, changes in body composition were seen from 5-12 weeks post-recombination. These data propose a critical role for skeletal muscle Bmal1 in both skeletal muscle glucose metabolism and overall body metabolic health. The presented findings also illuminate skeletal muscle Bmal1 and circadian rhythms as potential targets for metabolic disease.

Share

COinS