Wednesday, June 23, 2021
6/23/2021
7. Project Summary/Abstract Our previous studies identified the circadian clock component cryptochromes (CRY1 and CRY2) as nutrient responsive transcriptional regulators by virtue of their susceptibility to phosphorylation by AMP-activated protein kinase (AMPK). We have also described a function of CRY1 and CRY2 as diurnally active repressors of the glucocorticoid receptor, a prototypical member of a large family of transcriptional regulators known as nuclear hormone receptors (NRs). NRs are broadly important in modulating metabolic physiology and one member of this family, the so-called peroxisome proliferator activated receptor delta (PPARd) has been established as a critical driver of exercise capacity. We describe in our preliminary data here that CRY1 and CRY2 can repress PPARd and genetic deletion of Cry1 and Cry2 ubiquitously and throughout development results in enhanced sprint exercise capacity. In the course of our studies, we have generated unique tools and expertise that enable us to use biochemical, genetic, molecular and physiological approaches to further elucidate the roles of CRY1 and CRY2 in the regulation of PPARd and of exercise physiology in the following specific aims: 1) Does skeletal muscle drive enhanced exercise capacity in Cry1/2-deficient mice? 2) How does AMPK-mediated CRY1 phosphorylation impact exercise? and 3) What is the impact of Cry1/2 deletion or mutation on skeletal muscle cellular metabolism? Advancing our functional understanding of these interactions may highlight new therapeutic and regulatory strategies for preventing and/or treating disease.
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