Thesis Advisor:

Thomas J. Burkholder, PhD

Committee Members:

Mindy L. Millard-Stafford, PhD

Edward M. Balog, PhD

Young C. Jang, PhD

S. Russ Price, PhD

ABSTRACT
Metabolic flexibility is critical for muscle to maintain proper function and overall health. Muscle adapts to metabolic stress with increasing ATP synthesis by enhancing the rate of glycolysis and mitochondrial respiration. The control of that rate is mediated by several glucose metabolites. This project is based on the conceptual model that AMP indicates the balance of ATP synthesis and degradation, and NADH indicates the balance of glucose delivery to oxygen delivery. AMP signaling facilitates all aspects of glucose metabolism, and NAD+ signaling facilitates oxidative metabolism and inhibits reductive metabolism. The overall hypothesis is that the distribution of glucose depends on AMP and NAD+ generated during energetic stress.
The results suggest that glucose metabolism is highly sensitive to ATP homeostasis via AMPK activity. NADH oxidation alone is not sufficient to influence glucose oxidation, but require co-activation of AMPK. AMP and NAD+ signaling work independently in metabolic gene expression. The overall conclusion is that glucose metabolism depends on AMP signaling, but NAD signaling is unable to alter glucose disposal. AMP and NAD independently induced metabolic and differentiation adaptation. These findings suggest that other molecule may represent an additional gauge of aerobic and anaerobic metabolism.