# Regulation of Nutrient Sensing and Muscle Wasting by Alcohol

> **NIH NIH R37** · PENNSYLVANIA STATE UNIV HERSHEY MED CTR · 2020 · $333,162

## Abstract

Muscle wasting is a hallmark of sustained alcohol abuse and the associated weakness represents the most
common form of skeletal muscle myopathy. Over the past 4 years we have used genetic, biochemical and
pharmacological approaches, both in vivo and in vitro, to generate definitive evidence pertaining to the
mechanisms by which acute alcohol intoxication (binge drinking) and chronic alcohol consumption impair
muscle protein synthesis under basal postabsorptive conditions and antagonize the anabolic response to
amino acids and growth factors. The original 3 aims remain valid with experiments in the first phase of the R37
elucidating the cellular mechanisms by which alcohol down-regulates nutritional signals transduced via
mTORC1-dependent and -independent transduction networks producing skeletal muscle myopathy, and
comparing these to hormone- and contraction-induced regulation. Exceptional progress was made (27
publications) and the research environment leveraged for the successful training and F32 funding of a post-
doctoral fellow who will continue in alcohol-related research. Our publications attest that the original aims have
been largely achieved; although our new data also open previously unrecognized avenues of exploration.
Unique tools have been developed that will permit us to identify and explore novel mechanisms and thereby
validate specific proteins as therapeutic targets. Specific Aim 1 determined whether alcohol-induced changes
in Deptor are responsible for the decrease in basal and leucine-stimulated muscle protein synthesis. This aim
is now extended to investigate the relative importance of alcohol-induced changes in Deptor under in vivo
conditions using our newly developed muscle-specific Deptor knockout mouse. Further, our new data reveal
alcohol decreases the previously unrecognized binding of REDD1 with Deptor, a finding that will be expanded
upon. Specific Aim 2 delineated the mechanism by which alcohol alters mTOR endosomal trafficking thereby
impairing mTORC1 and protein synthesis. This aim will be continued by assessing alcohol-induced changes,
with and without leucine, on Sestrin2 phosphorylation and binding with proteins of the GATOR2 complex. The
goal of these experiments is to identify new components and modifiers governing the topology of mTORC1.
Specific Aim 3 elucidated whether altered MAP4K3 signaling is in part responsible for alcohol-induced
decreases mTORC1. These studies will be extended to examine the MAP4K3-dependent phosphorylation of
Raptor that can function by mTORC1-dependent and -independent mechanisms. This R37 extension exploits
innovative approaches, made possible by the availability of novel reagents and supported by our strong track
record. While in vitro studies permit us to define cellular mechanisms and prioritize future work, state-of-the-art
in vivo approaches permit us to definitively assign physiological importance – thus filling knowledge gaps. The
expected outcomes will contribute translati...

## Key facts

- **NIH application ID:** 9893775
- **Project number:** 5R37AA011290-25
- **Recipient organization:** PENNSYLVANIA STATE UNIV HERSHEY MED CTR
- **Principal Investigator:** CHARLES H. LANG
- **Activity code:** R37 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $333,162
- **Award type:** 5
- **Project period:** 2017-04-05 → 2022-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9893775

## Citation

> US National Institutes of Health, RePORTER application 9893775, Regulation of Nutrient Sensing and Muscle Wasting by Alcohol (5R37AA011290-25). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9893775. Licensed CC0.

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