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Acute Alcohol-Induced Decrease in Muscle Protein Synthesis in Female Mice Is REDD-1 and mTOR-Independent
Jennifer L Steiner1, Scot R Kimball1, Charles H Lang2
1Department of Cellular and Molecular Physiology, Penn State College of Medicine, 500 University Drive, Hershey, PA 17033, USA.
Aims:
To determine the causative role of the REDD (regulated in development and DNA damage)-1 protein, a known negative regulator of mTOR kinase, in changes in muscle protein synthesis induced by acute alcohol administration.
Methods:
Adult female REDD1(-/-) or wild-type (WT) mice were injected IP with ethanol (alcohol; 3 g/kg BW) or saline and the skeletal muscle was removed 1 h later. In vivo protein synthesis was assessed as were selected endpoints related to the activation of mTOR and protein degradation.
Results:
Acute alcohol decreased muscle protein synthesis similarly in WT and REDD1(-/-) mice. In contrast, mTORC1 signaling was largely unaffected by either EtOH or genotype as evidenced by the lack of change in the phosphorylation of its downstream targets, S6K1 T(389) and 4E-BP1 S(65). Although alcohol decreased p62 and ULK1 S(757) protein in muscle from WT and REDD1(-/-) mice, there was no change in LC3B lipidation, or beclin1, Atg7 and Atg12 protein suggesting no change in autophagy. MuRF1 and atrogin-1 mRNAs were elevated in alcohol-treated REDD1(-/-) mice compared with WT mice suggesting activation of the ubiquitin proteasome activity. While there was no genotype or alcohol effect on plasma corticosterone, REDD1(-/-) mice failed to demonstrate the alcohol-induced hyperinsulinemia seen in WT mice.
Conclusion:
REDD1 does not appear to play a role in the acute alcohol-mediated decrease in protein synthesis or mTOR activity, but may contribute to the regulation of ubiquitin-proteasome mediated protein breakdown.
Insights
Regulated in development and DNA damage-1 (REDD1) protein does not affect alcohol-induced muscle protein synthesis changes. However, REDD1 may play a role in alcohol-induced ubiquitin-proteasome mediated protein breakdown.
Area of Science:
- Muscle physiology and molecular biology
- Alcohol metabolism and its effects on cellular processes
- Protein synthesis and degradation pathways
Background:
- Acute alcohol consumption can impair muscle protein synthesis.
- The protein regulated in development and DNA damage-1 (REDD1) is a known negative regulator of mTOR kinase.
- The role of REDD1 in alcohol-induced muscle protein synthesis changes is not well understood.
Purpose of the Study:
- To investigate the role of REDD1 in alcohol-induced changes in muscle protein synthesis.
- To determine if REDD1 influences mTOR kinase activity following acute alcohol exposure.
- To examine the impact of REDD1 on protein degradation pathways after alcohol administration.
Main Methods:
- Adult female REDD1 knockout (REDD1-/-) and wild-type (WT) mice were administered ethanol (alcohol) or saline via intraperitoneal injection.
- Skeletal muscle was collected 1 hour post-injection for analysis.
- In vivo protein synthesis, mTORC1 signaling activation, and protein degradation markers were assessed.
Main Results:
- Acute alcohol administration decreased muscle protein synthesis similarly in both WT and REDD1-/- mice.
- Ethanol and genotype did not significantly alter mTORC1 signaling, as indicated by downstream target phosphorylation.
- While alcohol decreased certain autophagy-related proteins, markers of autophagy initiation and completion remained unchanged.
- Alcohol increased MuRF1 and atrogin-1 mRNA levels in REDD1-/- mice, suggesting increased ubiquitin-proteasome activity.
- REDD1-/- mice did not exhibit alcohol-induced hyperinsulinemia observed in WT mice.
Conclusions:
- REDD1 does not appear to mediate the acute alcohol-induced reduction in muscle protein synthesis or affect mTOR activity.
- REDD1 may contribute to the regulation of ubiquitin-proteasome-mediated protein breakdown in response to alcohol.
- The findings suggest a potential role for REDD1 in modulating protein degradation pathways rather than synthesis inhibition following acute alcohol exposure.
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