# Project 3: Sarcopenia of ALD: Regulation of Skeletal Muscle Autophagy by Alcohol

> **NIH NIH P50** · CLEVELAND CLINIC LERNER COM-CWRU · 2020 · $244,899

## Abstract

ABSTRACT 
The prevalence and incidence of alcoholic liver disease is increasing. Loss of skeletal muscle mass or 
sarcopenia is the most frequent complication of alcoholic liver disease and adversely affects survival, quality of 
life and development of other complications of liver disease. Sarcopenia is more severe and progresses more 
rapidly in alcoholic than in non-alcoholic patients. This suggests a direct effect of ethanol in addition to other 
consequences of liver disease in mediating sarcopenia. It is also known that alcohol related muscle loss and 
myopathy are five times more frequent than liver disease. Despite recognition of the high clinical significance, 
there are no therapeutic options primarily because the mechanisms of sarcopenia in alcoholic liver disease are 
not known. Reduced skeletal muscle protein synthesis by alcohol has been described in the past. However, 
since impaired protein synthesis alone is not enough to cause muscle loss, an increase in protein breakdown is 
also necessary for the development of sarcopenia in alcoholic liver disease. The ubiquitin-proteasome pathway 
and autophagy are two well-recognized mechanisms of skeletal muscle protein breakdown. We have 
previously reported that ethanol increases skeletal muscle mediated autophagy with unaltered or decreased 
proteasome activity. The goal of the present studies is to determine the molecular mechanisms responsible for 
ethanol mediated increase in skeletal muscle autophagy, to identify potential therapeutic targets and to perform 
clinical translational studies. Molecular and metabolic studies in a comprehensive array of models will be used 
in human subjects with alcoholic cirrhosis, and genetically modified mice and C2C12 muscle cells exposed to 
alcohol. Our preliminary studies showed that alcohol inhibits activation of mTOR, a known inhibitor of 
autophagy, and AMPK, that activates autophagy due to dephosphorylation of these counter-regulatory 
signaling molecules. We also observed that the activity of protein phosphatase 2A, a critical dephosphorylase, 
increased while the activity of its upstream inhibitor, PI3Kγ was reduced by alcohol. Finally, reactive oxygen 
species, generated by mitochondrial and microsomal alcohol metabolism, inhibits PI3Kγ. We therefore 
hypothesize that impaired PI3Kγ-PP2A axis mediates skeletal muscle autophagy in alcoholic liver disease. 
We will test this hypothesis by 2 specific aims to demonstrate that the mechanism of alcohol mediated 
impairment of the skeletal muscle PI3Kγ-PP2A axis is due to ROS generated from alcohol metabolism and 
increased dephosphorylation impairs downstream canonical mTOR targets with consequent increased 
autophagy and sarcopenia. Skeletal muscle from genetically modified mice with PI3Kγ knockout, CYP2E1 
knockout, in-vivo electroporation with constitutively active mTOR, murine myotubes exposed to alcohol and 
patients with alcoholic cirrhosis administered essential amino acids with excess le...

## Key facts

- **NIH application ID:** 9900710
- **Project number:** 5P50AA024333-05
- **Recipient organization:** CLEVELAND CLINIC LERNER COM-CWRU
- **Principal Investigator:** Srinivasan Dasarathy
- **Activity code:** P50 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $244,899
- **Award type:** 5
- **Project period:** — → 2021-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9900710

## Citation

> US National Institutes of Health, RePORTER application 9900710, Project 3: Sarcopenia of ALD: Regulation of Skeletal Muscle Autophagy by Alcohol (5P50AA024333-05). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/9900710. Licensed CC0.

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