Regulation of Protein Synthesis by Glucose

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PROJECT SUMMARY/ABSTRACT Skeletal muscle loss is associated with aging and various disease states. The mechanistic Target of Rapamycin in Complex 1 (mTORC1) is a protein kinase that acts to upregulate skeletal muscle protein synthesis and thereby promote muscle growth. Adenosine monophosphate-activated protein kinase (AMPK), a nutrient sensor, inhibits mTORC1 during nutrient depletion and thereby inhibits cellular growth. Similarly, the Sestrin family of proteins (Sestrins1-3) are leucine sensors that act to suppress mTORC1 by binding to and inhibiting the mTORC1 activating complex referred to as GAP activity toward Rags (GATOR2). Interestingly, the Sestrins bind not only to GATOR2 but also AMPK, suggesting that they may mediate leucine-induced activation of mTORC1 through multiple mechanisms. In novel preliminary studies presented herein, I show that the Sestrins mediate not only leucine, but also glucose signaling to mTORC1. However, which of the three Sestrins mediates glucose-induced regulation of mTORC1 is unknown. Moreover, whether glucose-induced activation of mTORC1 is mediated through the Sestrin-GATOR2 complex and/or the Sestrin-AMPK complex is unexplored. Previous studies have shown that AMPK is not only regulated by glucose but that it also regulates glucose metabolism, e.g. it upregulates hexokinase 2 (HKII) expression, suppresses glycogen synthesis, and promotes glycogenolysis. In novel preliminary studies presented herein, I show a specific interaction of Sestrin3 with AMPK and also show that Sestrin3 associates with HKII. Based on these findings, I propose to test the hypothesis that glucose acts through Sestrin3 and HKII to both stimulate mTORC1 activity and promote glycogenolysis. By using knockdown and overexpression cell culture and rodent models as well as advanced microscopy techniques I will elucidate the mechanisms through which glucose acts to modulate skeletal muscle protein synthesis and glucose metabolism. It is anticipated that delineation of the molecular markers associated with glucose-mediated stimulation of skeletal muscle metabolism will provide novel targets for future studies as well as targets for pharmaceutical manipulation.