Circadian control of nutrient-sensing and fuel utilization in skeletal muscle

Circadian systems play a central role in energy harvesting and storage across daily cycles of fuel availability in nearly all organisms. In vertebrates, clock genes promote metabolic constancy by coordinating the phase and expression of genes involved in glycolytic and oxidative metabolism. Genetic studies demonstrate that the clock network exerts alternating effects on physiology at different times of day in a tissue-specific manner. A major clue concerning the role of the clock signaling network during fasting and nutrient deprivation stems from our recently published discovery (Science, 2013) that circadian transcription factors directly control cellular levels of NAD+ and activity of NAD+-dependent metabolic regulators. We have uncovered a novel pathway by which the circadian clock control of NAD+ impacts mitochondrial metabolism through rhythms of NAD+-dependent processes, including protein deacetylation via the mitochondrial sirtuin SIRT3. However, it is still unclear whether the circadian clock controls daily transitions of oxidative and glycolytic fuel utilization in all metabolic tissues, and whether abrogation of this pathway leads to impaired whole animal metabolic physiology. To address this question, I propose to dissect the role of circadian factors in metabolic fuel handling and the response to nutrient stress (e.g exercise, fasting) in skeletal muscle, a tissue that undergoes dramatic daily fluctuations in nutrient availability due to rhythmic behaviors such as feeding and locomotor activity. Specifically, I propose to focus on the interplay between circadian clocks and two key nutrient stress response pathways: the NAD+/sirtuin axis and the hypoxic stress response (HIF) transcriptional network. The overarching goal for this proposal is to provide new insight into the homeostatic link between biological timing and nutrient sensing pathways with implications for the treatment of metabolic disease including skeletal myopathy and diabetes.