Acute Alcohol-Induced Decrease in Muscle Protein Synthesis in Female Mice Is REDD-1 and mTOR-Independent.

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.
(© The Author 2015. Medical Council on Alcohol and Oxford University Press. All rights reserved.)