Abstract
BackgroundAcute alcohol (EtOH) intoxication decreases muscle protein synthesis via inhibition of mTOR-dependent translation initiation. However, these studies have been performed in relatively young rapidly growing rats in which muscle protein accretion is more sensitive to growth factor and nutrient stimulation. Furthermore, some in vivo-produced effects of EtOH vary in an age-dependent manner. The hypothesis tested in the present study was that young rats will show a more pronounced decrement in muscle protein synthesis than older mature rats in response to acute EtOH intoxication.MethodsMale F344 rats were studied at approximately 3 (young) or 12 (mature) months of age. Young rats were injected intraperitoneally with 75 mmol/kg of EtOH, and mature rats injected with either 75 or 90 mmol/kg EtOH. Time-matched saline-injected control rats were included for both age groups. Gastrocnemius protein synthesis and the activity of the mTOR pathway were assessed 2.5 h after EtOH using [3H]-labeled phenylalanine and the phosphorylation of various protein factors known to regulate peptide-chain initiation.ResultsBlood alcohol levels (BALs) were lower in mature rats compared to young rats after administration of 75 mmol/kg EtOH (154 ± 23 vs 265 ± 24 mg/dL). However, injection of 90 mmol/kg EtOH in mature rats produced BALs comparable to that of young rats (281 ± 33 mg/dL). EtOH decreased muscle protein synthesis similarly in both young and high-dose EtOH-treated mature rats. The EtOH-induced changes in both groups were associated with a concomitant reduction in 4E-BP1 phosphorylation, and redistribution of eIF4E between the active eIF4E·eIF4G and inactive eIF4E·4EBP1 complex. Moreover, EtOH increased the binding of mTOR with raptor in a manner which appeared to be AMPK- and TSC-independent. In contrast, although muscle protein synthesis was unchanged in mature rats given low-dose EtOH, compared to control values, the phosphorylation of rpS6 and eIF4G was decreased.ConclusionThese data indicate that muscle protein synthesis is equally sensitive to the inhibitory effects of EtOH in young rapidly growing rats and older mature rats which are growing more slowly, but that mature rats must be given a relatively larger dose of EtOH to achieve the same BAL. Based on the differential response in mature rats to low- and high-dose EtOH, the decreased protein synthesis was associated with a reduction in mTOR activity which was selectively mediated via a reduction in 4E-BP1 phosphorylation and an increase in mTOR·raptor formation.
Highlights
Acute alcohol (EtOH) intoxication decreases muscle protein synthesis via inhibition of mammalian Target Of Rapamycin (mTOR)-dependent translation initiation
Results from the present study indicate muscle protein synthesis in young adult and mature F344 rats is sensitive to the suppressive effect of acute alcohol intoxication
The alcoholinduced decrease in muscle protein synthesis produced by acute intoxication is not limited to rapidly growing animals as long as comparisons between different aged rats are matched to the prevailing blood alcohol level and not the dose of alcohol administered
Summary
Acute alcohol (EtOH) intoxication decreases muscle protein synthesis via inhibition of mTOR-dependent translation initiation. Acute alcohol intoxication decreases muscle protein synthesis in a dose- and time-dependent manner, and this response is largely if not completely abated 24 h after alcohol administration [1,2] This alcohol-induced decrease is independent of the oxidative metabolism of ethanol and cannot be explained by the over production of either glucocorticoids or selected proinflammatory cytokines, such as tumor necrosis factor (TNF)-α, interleukin (IL)-1 or IL-6 [1,3,4]. Our data suggested that the mammalian Target Of Rapamycin (mTOR) played a central role in regulating the alcohol-induced decrease in muscle protein synthesis [1,6,7] The activity of this serine (Ser)/Thr kinase is most often assessed by phosphorylation of its immediate down stream substrates namely ribosomal protein S6 kinase (S6K1)-1 and the eukaryotic initiation factor 4E (eIF-4E) binding protein-1 (4E-BP1) [8]. The mechanism by which alcohol impairs mTOR activity is poorly defined
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