Jennifer L Steiner1, Scot R Kimball1, Charles H Lang2. 1. Department of Cellular and Molecular Physiology, Penn State College of Medicine, 500 University Drive, Hershey, PA 17033, USA. 2. Department of Cellular and Molecular Physiology, Penn State College of Medicine, 500 University Drive, Hershey, PA 17033, USA clang@psu.edu.
Abstract
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.
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.
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