Alcohol impairs leucine-mediated phosphorylation of 4E-BP1, S6K1, eIF4G, and mTOR in skeletal muscle

Lang, Charles H.; Frost, Robert A.; Deshpande, Nobuko; Kumar, Vinayshree; Vary, Thomas C.; Jefferson, Leonard S.; Kimball, Scot R.

doi:10.1152/ajpendo.00177.2003

Cited by 96 publications

(178 citation statements)

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“…This amount of leucine approximates that consumed in a 24-h period when rats of this age and strain are provided free access to chow (1). Furthermore, this amount of leucine increases muscle protein synthesis by stimulating translation initiation (1,23,25).…”

Section: Methodsmentioning

confidence: 77%

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Elevated plasma free fatty acids decrease basal protein synthesis, but not the anabolic effect of leucine, in skeletal muscle

Lang¹

2006

American Journal of Physiology-Endocrinology and Metabolism

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Lang, Charles H. Elevated plasma free fatty acids decrease basal protein synthesis, but not the anabolic effect of leucine, in skeletal muscle. Am J Physiol Endocrinol Metab 291: E666 -E674, 2006. First published May 9, 2006; doi:10.1152/ajpendo.00065.2006.-Elevations in free fatty acids (FFAs) impair glucose uptake in skeletal muscle. However, there is no information pertaining to the effect of elevated circulating lipids on either basal protein synthesis or the anabolic effects of leucine and insulin-like growth factor I (IGF-I). In chronically catheterized conscious rats, the short-term elevation of plasma FFAs by the 5-h infusion of heparin plus Intralipid decreased muscle protein synthesis by ϳ25% under basal conditions. Lipid infusion was associated with a redistribution of eukaryotic initiation factor (eIF)4E from the active eIF4E ⅐ eIF4G complex to the inactive eIF4E ⅐ 4E-BP1 complex. This shift was associated with a decreased phosphorylation of eIF4G but not 4E-BP1. Lipid infusion did not significantly alter either the total amount or phosphorylation state of mTOR, TSC2, S6K1, or the ribosomal protein S6 under basal conditions. In control rats, oral leucine increased muscle protein synthesis. This anabolic response was not impaired by lipid infusion, and no defects in signal transduction pathways regulating translation initiation were detected. In separate rats that received a bolus injection of IGF-I, lipid infusion attenuated the normal redistribution of eIF4E from the active to inactive complex and largely prevented the increased phosphorylation of 4E-BP1, eIF4G, S6K1, and S6. This IGF-I resistance was associated with enhanced Ser 307 phosphorylation of insulin receptor substrate-1 (IRS-1). These data indicate that the short-term elevation of plasma FFAs impairs basal protein synthesis in muscle by altering eIF4E availability, and this defect may be related to impaired phosphorylation of eIF4G, not 4E-BP1. Moreover, hyperlipidemia impairs IGF-I action but does not produce leucine resistance in skeletal muscle. leucine; insulin-like growth factor I; eukaryotic initiation factor 4E-binding protein-1; eukaryotic initiation factor 4G; mammalian target of rapamycin; tuberous sclerosis complex 2 IN CONTRAST TO THE EXTENSIVE LITERATURE on the relationship between circulating free fatty acids (FFAs) and glucose metabolism, there is a paucity of information pertaining to the impact of FFAs on protein metabolism. Early studies where plasma FFAs were acutely increased by infusion of Intralipid plus heparin (9) reported a generalized hypoaminoacidemia. This response demonstrates a mismatch between the rates of appearance and disappearance of amino acids and suggests that elevated plasma FFAs increase protein synthesis and/or decrease proteolysis. This protein-sparing effect of lipid was confirmed in isotope dilution studies where radiolabeled leucine was used, which concluded that increased FFA availability was inversely related to the rate of whole body proteolysis (e.g., decreased rate of leucine appearance) b...

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Section: Methodsmentioning

confidence: 77%

“…In addition to serving as a substrate for protein synthesis, amino acids stimulate cell signaling pathways important in the regulation of translational efficiency (20,25,28). Under in vivo conditions and in the isolated perfused muscle preparation, amino acids enhance protein synthesis by increasing the rate of translation initiation (27,30).…”

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confidence: 99%

Elevated plasma free fatty acids decrease basal protein synthesis, but not the anabolic effect of leucine, in skeletal muscle

Lang¹

2006

American Journal of Physiology-Endocrinology and Metabolism

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“…However, if sedentarism and disuse atrophy is induced by casting of a limb, alcohol consumption will enhance muscle loss by 80%, in association with increased expression of atrogin-1 mRNA, reduction in 4E-BP1 and S6 phosphorylation, and increased AMP-activated kinase phosphorylation (26) . Even in freely-moving rats, alcohol intoxication might blunt the anabolic effects of amino acids in muscle tissue, nominally in the form of leucine resistance, as evidenced by the impaired phosphorylation of 4E-BP1, eIF4G, S6K1, and mTOR (18) . Persistent inflammation could also be a trigger of muscle wasting, as demonstrated not only in serious illnesses such as dialysis-requiring renal disease, heart insufficiency and chronic obstructive lung disease, but also in the standard aging process.…”

Section: Discussionmentioning

confidence: 99%

Nutritional profile of asymptomatic alcoholic patients

Sobral-Oliveira¹,

Faintuch²,

Guarita³

et al. 2011

Arq. Gastroenterol.

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-Context -Alcoholism may interfere with nutritional status, but reports are often troubled by uncertainties about ingested diet and organ function, as well as by ongoing abuse and associated conditions. Objective -To identify nutritional and body compartment changes in stable alcoholics without confounding clinical and dietetic variables, a prospective observational pilot study was designed. Three well-matched populations were considered: subjects with chronic alcoholic pancreatitis, alcoholics without visceral disease, and healthy never-drinking adults (controls). Methods -Subjects (n = 60) were asymptomatic males with adequate diet, no superimposed disease or complication, and alcohol-free for at least 6 months. After exclusions, 48 patients were compared. Variables encompassed dietary recall, bioimpedance analysis, biochemical profile and inflammatory markers. Main outcome measures were body fat, lean body mass, serum lipids, C-reactive protein, and selected minerals and vitamins. Results -Both alcoholic populations suffered from reduced lean body mass (P = 0.001), with well-maintained body fat. Magnesium was depleted, and values of vitamin D and B12 correlated with alcohol abuse. LDL and total cholesterol was increased in alcoholics without pancreatitis (P = 0.04), but not in those with visceral damage. C-reactive protein and serum amyloid A correlated with duration of excessive drinking (P = 0.01).Conclusions -Undernutrition (diminished lean body mass, risk of magnesium and vitamin deficiencies) contrasted with dyslipidemia and increased cardiovascular risk. This second danger was masked during chronic pancreatitis but not in alcoholics without visceral disease. Further studies should focus special requirements of this population.

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“…The eIF4E·eIF4G complexes were quantified as described (40,42). Briefly, eIF4E was immunoprecipitated from aliquots of supernatants using an anti-eIF4E monoclonal antibody.…”

Section: Methodsmentioning

confidence: 99%

Chronic alcohol consumption disrupts myocardial protein balance and function in aged, but not adult, female F344 rats

Lang

2014

American Journal of Physiology-Regulatory, Integrative and Comp

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Lang CH, Korzick DH. Chronic alcohol consumption disrupts myocardial protein balance and function in aged, but not adult, female F344 rats. Am J Physiol Regul Integr Comp Physiol 306: R23-R33, 2014. First published November 13, 2013 doi:10.1152/ajpregu.00414.2013.-The purpose of this study was to assess whether the deleterious effect of chronic alcohol consumption differs in adult and aged female rats. To address this aim, adult (4 mo) and aged (18 mo) F344 rats were fed a nutritionally complete liquid diet containing alcohol (36% total calories) or an isocaloric isonitrogenous control diet for 20 wk. Cardiac structure and function, assessed by echocardiography, as well as myocardial protein synthesis and proteolysis did not differ in either alcohol-versus control-fed adult rats or in adult versus aged controlfed rats. In contrast, cardiac function was impaired in alcohol-fed aged rats compared with age-matched control rats. Additionally, alcohol feeding decreased cardiac protein synthesis that was associated with decreased phosphorylation of 4E-BP1 and S6K1. This reduction in mammalian target of rapamycin (mTOR) kinase activity was associated with reduced eIF3f and binding of both Raptor and eIF4G to eIF3. Proteasome activity was increased in alcohol-fed aged rats with a coordinate elevation in the E3 ligases atrogin-1 and muscle RINGfinger protein-1 (MuRF1). These changes were associated with increased regulated in development and DNA damage response 1 (REDD1) and phosphorylation of AMP-activated protein kinase (AMPK) but no increase in AKT or forkhead transcription factor (FOXO)3 phosphorylation. Finally, markers of autophagy (e.g., LC3B, Atg7, Atg12) and TNF-␣ were increased to a greater extent in alcohol-fed aged rats. These data demonstrate that aged female rats exhibit an enhanced sensitivity to alcohol compared with adult animals. Our data are consistent with a model whereby alcohol increases proteolysis via FOXO-independent increase in atrogin-1, which degrades eIF3f and therefore impairs formation of a functional preinitiation complex and protein synthesis.

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Alcohol impairs leucine-mediated phosphorylation of 4E-BP1, S6K1, eIF4G, and mTOR in skeletal muscle

Cited by 96 publications

References 48 publications

Elevated plasma free fatty acids decrease basal protein synthesis, but not the anabolic effect of leucine, in skeletal muscle

Elevated plasma free fatty acids decrease basal protein synthesis, but not the anabolic effect of leucine, in skeletal muscle

Nutritional profile of asymptomatic alcoholic patients

Chronic alcohol consumption disrupts myocardial protein balance and function in aged, but not adult, female F344 rats

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