# Regulation of Protein Synthesis by Glucose

> **NIH NIH F32** · PENNSYLVANIA STATE UNIV HERSHEY MED CTR · 2020 · $64,926

## Abstract

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.

## Key facts

- **NIH application ID:** 10141415
- **Project number:** 1F32DK126312-01A1
- **Recipient organization:** PENNSYLVANIA STATE UNIV HERSHEY MED CTR
- **Principal Investigator:** Paul A Roberson
- **Activity code:** F32 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $64,926
- **Award type:** 1
- **Project period:** 2020-09-01 → 2023-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10141415

## Citation

> US National Institutes of Health, RePORTER application 10141415, Regulation of Protein Synthesis by Glucose (1F32DK126312-01A1). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10141415. Licensed CC0.

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