Roberto Vargas1, Charles H Lang. 1. Department of Cellular and Molecular Physiology, Pennsylvania State University College of Medicine, Hershey, Pennsylvania 17033, USA.
Abstract
BACKGROUND: Muscle disuse atrophy is observed in patients recovering from trauma and there is an increased risk and severity of injury in patients abusing alcohol (EtOH). However, the interaction of EtOH and disuse on muscle protein balance has not been examined. Therefore, the present study addressed the hypothesis that EtOH accelerates the disuse atrophy and/or impairs the accretion of muscle protein during muscle recovery. METHODS: To address this aim, disuse atrophy was induced in rats by 3 days of unilateral hindlimb immobilization (casting), using the contralateral leg as control, with EtOH or saline being orally gavaged twice, each day during this period. In a separate study, EtOH-treated rats received Velcade to inhibit proteasomal degradation. Finally, in the last study, rats had 1 limb casted for 5 days, the cast removed, and EtOH or saline gavaged twice daily during a 5-day recovery period. Muscle protein metabolism was assessed using surrogate markers of protein synthesis [i.e., phosphorylation of 4E-binding protein 1 (BP1) and S6 kinase 1 (S6K1)] and protein degradation (i.e., mRNA content of the ubiquitin E3 ligases atrogin-1 and MuRF1). RESULTS: Ethanol alone did not decrease muscle weight in the uncasted muscle. However, the loss of mass of immobilized muscle from EtOH-gavaged rats was 80% greater than in the animals not receiving EtOH. This atrophic response was not associated with a change in Akt, 4E-BP1 or S6K1 phosphorylation among groups. In contrast, immobilization alone increased both atrogin-1 and MuRF1 mRNA, and EtOH further increased their expression in immobilized muscle. The proteasome inhibitor Velcade attenuated atrophy produced by EtOH + disuse. When administered during the recovery period, EtOH prevented the normal accretion of muscle mass. This EtOH effect was associated with increased atrogin-1 mRNA, a reduction in 4E-BP1 and S6 phosphorylation, and an increased AMP-activated kinase phosphorylation. CONCLUSIONS: Based on the changes in these surrogate markers, our data suggest that EtOH accelerates disuse atrophy by stimulating ubiquitin-mediated proteolysis, and blunts repletion of muscle protein during recovery from disuse by increasing proteolysis and decreasing protein synthesis.
BACKGROUND: Muscle disuse atrophy is observed in patients recovering from trauma and there is an increased risk and severity of injury in patients abusing alcohol (EtOH). However, the interaction of EtOH and disuse on muscle protein balance has not been examined. Therefore, the present study addressed the hypothesis that EtOH accelerates the disuse atrophy and/or impairs the accretion of muscle protein during muscle recovery. METHODS: To address this aim, disuse atrophy was induced in rats by 3 days of unilateral hindlimb immobilization (casting), using the contralateral leg as control, with EtOH or saline being orally gavaged twice, each day during this period. In a separate study, EtOH-treated rats received Velcade to inhibit proteasomal degradation. Finally, in the last study, rats had 1 limb casted for 5 days, the cast removed, and EtOH or saline gavaged twice daily during a 5-day recovery period. Muscle protein metabolism was assessed using surrogate markers of protein synthesis [i.e., phosphorylation of 4E-binding protein 1 (BP1) and S6 kinase 1 (S6K1)] and protein degradation (i.e., mRNA content of the ubiquitin E3 ligases atrogin-1 and MuRF1). RESULTS:Ethanol alone did not decrease muscle weight in the uncasted muscle. However, the loss of mass of immobilized muscle from EtOH-gavaged rats was 80% greater than in the animals not receiving EtOH. This atrophic response was not associated with a change in Akt, 4E-BP1 or S6K1 phosphorylation among groups. In contrast, immobilization alone increased both atrogin-1 and MuRF1 mRNA, and EtOH further increased their expression in immobilized muscle. The proteasome inhibitor Velcadeattenuated atrophy produced by EtOH + disuse. When administered during the recovery period, EtOH prevented the normal accretion of muscle mass. This EtOH effect was associated with increased atrogin-1 mRNA, a reduction in 4E-BP1 and S6 phosphorylation, and an increased AMP-activated kinase phosphorylation. CONCLUSIONS: Based on the changes in these surrogate markers, our data suggest that EtOH accelerates disuse atrophy by stimulating ubiquitin-mediated proteolysis, and blunts repletion of muscle protein during recovery from disuse by increasing proteolysis and decreasing protein synthesis.
Authors: Flavia M Souza-Smith; Charles H Lang; Laura E Nagy; Shannon M Bailey; Loren H Parsons; Gary J Murray Journal: Am J Physiol Endocrinol Metab Date: 2016-07-19 Impact factor: 4.310
Authors: Elisa I Glover; Stuart M Phillips; Bryan R Oates; Jason E Tang; Mark A Tarnopolsky; Anna Selby; Kenneth Smith; Michael J Rennie Journal: J Physiol Date: 2008-10-27 Impact factor: 5.182