MYOCARDIAL PROTEIN SYNTHESIS AFTER ALCOHOL INTOXICATION

Summary

Principal Investigator: Charles Lang
Abstract: DESCRIPTION (provided by applicant): The long-term goal of this project is to understand the mechanisms by which alcohol consumption induces myofibrillar damage characteristic of alcoholic heart muscle disease. Alcoholism remains the most common form of drug abuse in the United States. Alcohol abuse is associated with an increased premature mortality partly resulting from the development of an alcohol-induced cardiomyopathy, a condition diagnosed in approximately 35% of whose individuals who chronically consume excessive amounts of alcohol. The mechanisms leading to alcohol-dependent myocardial dysfunction are multifactorial, but altered expression of myocardial proteins appears as a central mechanism. Studies completed during the current funding period established that alcohol consumption inhibits rates of protein synthesis in heart at the level of mRNA translation. By understanding the alterations in the process of mRNA translation it is hoped that new strategies could be developed to combat the pathologic derangements in cardiac muscle structure and function associated with chronic alcoholism. We delineated two regulatory steps in the process of protein synthesis, the formation of an active elF4E-elF4G complex and the process of elongation that are responsible, in part, for the inhibition of protein synthesis during chronic alcohol administration, whereas acute alcohol intoxication only affects the formation of an active elF4E-elF4G complex. We hypothesize that the normal signaling path-way through mTOR responsible for maintaining the functioning of these two steps in protein synthesis at rates observed in control animals is severely compromised by ethanol intake. The net effect is manifested through alterations in the expression of myocardial proteins including contractile proteins. We further hypothesize that provision of amino acids either through acute gavage or meal feeding to rats administered alcohol can stimulate mTOR leading to an acceleration of rates of protein synthesis. The experimental design for the forthcoming project period addresses the following Specific Aims in order to test the hypothesis that: 1) Alcohol consumption reduces mTOR activity resulting in dephosphorylation of 4E-BP1 and S6K1, thereby limiting myocardial protein synthesis by reducing formation of active elF4G-elF4E complex;2) Stimulating mTOR activity with aminp acid supplementation reverses the alcohol-induced inhibition of myocardial protein synthesis;3) Inhibition of protein synthesis in response to chronic alcohol feeding shifts myocardial protein expression;and 4) Genetic ablation of mTOR causes functional and biochemical derangements in the myocardium similar to those observed with chronic alcohol intake. Overall, the research design will establish the mechanism by which myocardial protein synthesis is reduced in response to alcohol abuse.
Funding Period: ----------------2000 - ---------------2011-
more information: NIH RePORT

Top Publications

  1. ncbi Leucine in food mediates some of the postprandial rise in plasma leptin concentrations
    Christopher J Lynch
    Dept of Cellular and Molecular Physiology, The Pennsylvania State University College of Medicine, Hershey, PA 17033, USA
    Am J Physiol Endocrinol Metab 291:E621-30. 2006
  2. pmc Skeletal and cardiac myopathy in HIV-1 transgenic rats
    Anne M Pruznak
    Department of Cellular and Molecular Physiology, The Pennsylvania State University College of Medicine, Hershey, Pennsylvania 17033, USA
    Am J Physiol Endocrinol Metab 295:E964-73. 2008
  3. pmc Partial dissociation of TSC2 and mTOR phosphorylation in cardiac and skeletal muscle of rats in vivo
    Sara Forsyth
    Department of Cellular and Molecular Physiology, Penn State University College of Medicine, The Milton S Hershey Medical Center, Hershey, PA 17033, USA
    Mol Cell Biochem 319:141-51. 2008
  4. pmc Acute alcohol intoxication increases atrogin-1 and MuRF1 mRNA without increasing proteolysis in skeletal muscle
    Thomas C Vary
    Department of Cellular and Molecular Physiology H166, Penn State College Medicine, 500 University Dr, Hershey, PA 17033, USA
    Am J Physiol Regul Integr Comp Physiol 294:R1777-89. 2008
  5. ncbi Assessing effects of alcohol consumption on protein synthesis in striated muscles
    Thomas C Vary
    Department of Cellular and Molecular Physiology, Pennsylvania State University College of Medicine, Hershey, PA, USA
    Methods Mol Biol 447:343-55. 2008
  6. ncbi Acute alcohol intoxication increases REDD1 in skeletal muscle
    Charles H Lang
    Department of Cellular and Molecular Physiology, Penn State University College of Medicine, Hershey, Pennsylvania 17033, USA
    Alcohol Clin Exp Res 32:796-805. 2008
  7. ncbi Differential phosphorylation of translation initiation regulators 4EBP1, S6k1, and Erk 1/2 following inhibition of alcohol metabolism in mouse heart
    Thomas C Vary
    Department of Cellular and Molecular Physiology, The Pennsylvania State University College of Medicine, Rm C4710, H166, 500 University Drive, Hershey, PA 17033, USA
    Cardiovasc Toxicol 8:23-32. 2008
  8. ncbi Chronic alcohol feeding impairs mTOR(Ser 2448) phosphorylation in rat hearts
    Thomas C Vary
    Department of Cellular and Molecular Physiology, The Pennsylvania State University College of Medicine, Hershey, Pennsylvania 17033, USA
    Alcohol Clin Exp Res 32:43-51. 2008
  9. pmc Disruption of BCATm in mice leads to increased energy expenditure associated with the activation of a futile protein turnover cycle
    Pengxiang She
    Department of Cellular and Molecular Physiology, The Pennsylvania State University College of Medicine, Hershey, PA 17033, USA
    Cell Metab 6:181-94. 2007
  10. ncbi Meal feeding stimulates phosphorylation of multiple effector proteins regulating protein synthetic processes in rat hearts
    Thomas C Vary
    Department of Cellular and Molecular Physiology, Penn State University College of Medicine, Hershey, PA 17033, USA
    J Nutr 136:2284-90. 2006

Scientific Experts

  • Emanuele Giordano
  • THOMAS VARY
  • Charles H Lang
  • Christopher J Lynch
  • Pengxiang She
  • Robert A Frost
  • Vance L Albaugh
  • Rachel L Fogle
  • Ali Nairizi
  • Sara Forsyth
  • Anne M Pruznak
  • Susan M Hutson
  • John L Joyal
  • STEVEN BREAZEALE
  • Olga Ilkayeva
  • Tedd D Elich
  • Brett R Wenner
  • Kevin P Maresca
  • Gina Deiter
  • Mary Palopoli
  • Bruce A Stanley
  • Ly Hong-Brown
  • Rachel Lantry
  • Sarah K Bronson
  • Tanya M Reid
  • Andras Hajnal
  • Beth Gern
  • Carolyn Lloyd
  • Rachel Eicher

Detail Information

Publications19

  1. ncbi Leucine in food mediates some of the postprandial rise in plasma leptin concentrations
    Christopher J Lynch
    Dept of Cellular and Molecular Physiology, The Pennsylvania State University College of Medicine, Hershey, PA 17033, USA
    Am J Physiol Endocrinol Metab 291:E621-30. 2006
    ..Thus Leu appears to regulate most of the effects of dietary amino acids on the postprandial rise in plasma leptin but is responsible only for part of the leptin response to meal feeding...
  2. pmc Skeletal and cardiac myopathy in HIV-1 transgenic rats
    Anne M Pruznak
    Department of Cellular and Molecular Physiology, The Pennsylvania State University College of Medicine, Hershey, Pennsylvania 17033, USA
    Am J Physiol Endocrinol Metab 295:E964-73. 2008
    ..Hence, HIV-1 Tg rats develop atrophy of cardiac and skeletal muscle, the latter of which results primarily from an increased protein degradation and may be related to the marked reduction in muscle insulin-like growth factor I...
  3. pmc Partial dissociation of TSC2 and mTOR phosphorylation in cardiac and skeletal muscle of rats in vivo
    Sara Forsyth
    Department of Cellular and Molecular Physiology, Penn State University College of Medicine, The Milton S Hershey Medical Center, Hershey, PA 17033, USA
    Mol Cell Biochem 319:141-51. 2008
    ..However, mTOR(Ser(2448)) or mTOR(Ser(2481)) phosphorylation was not elevated until the plasma insulin concentration reached 97 ng/ml. The results indicate there is a dissociation of TSC2 and mTOR phosphorylation in vivo...
  4. pmc Acute alcohol intoxication increases atrogin-1 and MuRF1 mRNA without increasing proteolysis in skeletal muscle
    Thomas C Vary
    Department of Cellular and Molecular Physiology H166, Penn State College Medicine, 500 University Dr, Hershey, PA 17033, USA
    Am J Physiol Regul Integr Comp Physiol 294:R1777-89. 2008
    ..Therefore, the loss of muscle mass/protein in response to chronic alcohol abuse appears to result primarily from a decrement in muscle protein synthesis, not an increase in degradation...
  5. ncbi Assessing effects of alcohol consumption on protein synthesis in striated muscles
    Thomas C Vary
    Department of Cellular and Molecular Physiology, Pennsylvania State University College of Medicine, Hershey, PA, USA
    Methods Mol Biol 447:343-55. 2008
    ..The methods can be modified for studies involving transgenic mice allowing mechanisms responsible for the defects in protein synthesis to be dissected...
  6. ncbi Acute alcohol intoxication increases REDD1 in skeletal muscle
    Charles H Lang
    Department of Cellular and Molecular Physiology, Penn State University College of Medicine, Hershey, Pennsylvania 17033, USA
    Alcohol Clin Exp Res 32:796-805. 2008
    ..In this regard, mTOR activity is impaired after over expression of the regulatory protein REDD1. Hence, the present study assessed the ability of REDD1 as a potential mediator of the EtOH-induced decrease in muscle protein synthesis...
  7. ncbi Differential phosphorylation of translation initiation regulators 4EBP1, S6k1, and Erk 1/2 following inhibition of alcohol metabolism in mouse heart
    Thomas C Vary
    Department of Cellular and Molecular Physiology, The Pennsylvania State University College of Medicine, Rm C4710, H166, 500 University Drive, Hershey, PA 17033, USA
    Cardiovasc Toxicol 8:23-32. 2008
    ....
  8. ncbi Chronic alcohol feeding impairs mTOR(Ser 2448) phosphorylation in rat hearts
    Thomas C Vary
    Department of Cellular and Molecular Physiology, The Pennsylvania State University College of Medicine, Hershey, Pennsylvania 17033, USA
    Alcohol Clin Exp Res 32:43-51. 2008
    ....
  9. pmc Disruption of BCATm in mice leads to increased energy expenditure associated with the activation of a futile protein turnover cycle
    Pengxiang She
    Department of Cellular and Molecular Physiology, The Pennsylvania State University College of Medicine, Hershey, PA 17033, USA
    Cell Metab 6:181-94. 2007
    ..These observations suggest that elevated BCAAs and/or loss of BCAA catabolism in peripheral tissues play an important role in regulating insulin sensitivity and energy expenditure...
  10. ncbi Meal feeding stimulates phosphorylation of multiple effector proteins regulating protein synthetic processes in rat hearts
    Thomas C Vary
    Department of Cellular and Molecular Physiology, Penn State University College of Medicine, Hershey, PA 17033, USA
    J Nutr 136:2284-90. 2006
    ....
  11. ncbi Sex-dependent differences in the regulation of myocardial protein synthesis following long-term ethanol consumption
    Thomas C Vary
    Department of Cellular and Molecular Physiology, Penn State University College of Medicine, H166, 500 University Dr, Hershey, PA 17033, USA
    Am J Physiol Regul Integr Comp Physiol 292:R778-87. 2007
    ..The failure of female rats consuming ethanol to show structural changes appears related to the inability of ethanol to affect the regulation protein synthesis to the same extent as their male counterparts...
  12. ncbi Skeletal muscle protein synthesis and degradation exhibit sexual dimorphism after chronic alcohol consumption but not acute intoxication
    Charles H Lang
    Department of Cellular and Molecular Physiology, The Pennsylvania State University College of Medicine, Hershey, Pennsylvania, PA 17033, USA
    Am J Physiol Endocrinol Metab 292:E1497-506. 2007
    ....
  13. ncbi Nutrient signaling components controlling protein synthesis in striated muscle
    Thomas C Vary
    Department of Cellular and Molecular Physiology, Pennsylvania State University College of Medicine, Hershey, PA 17033, USA
    J Nutr 137:1835-43. 2007
    ....
  14. ncbi Rapamycin limits formation of active eukaryotic initiation factor 4F complex following meal feeding in rat hearts
    Thomas C Vary
    Department of Cellular and Molecular Physiology, Pennsylvania State University College of Medicine, Hershey, PA 17033, USA
    J Nutr 137:1857-62. 2007
    ..Furthermore, the rapamycin-sensitive reductions in phosphorylation of eIF4G may also lead to decreased formation of active eIF4G-eIF4E complex...
  15. pmc Leucine supplementation of drinking water does not alter susceptibility to diet-induced obesity in mice
    Ali Nairizi
    Penn State Hershey Institute for Diabetes and Obesity and Department of Cellular and Molecular Physiology, Pennsylvania State University College of Medicine, Hershey, PA 17033, USA
    J Nutr 139:715-9. 2009
    ..Taken together, the results do not provide evidence that either Leu or BCAA supplementation of drinking water ameliorates diet-induced obesity in mice, although it may improve glycemia...
  16. pmc Oral leucine enhances myocardial protein synthesis in rats acutely administered ethanol
    Thomasc Vary
    Department of Cellular and Molecular Physiology, Penn State University College of Medicine, Hershey, PA 17033, USA
    J Nutr 139:1439-44. 2009
    ..Leu gavage accelerates myocardial protein synthesis following acute ethanol intoxication by enhancing eIF4G.eIF4E complex assembly through increased phosphorylation of eIF4G and decreased association of 4EBP1 with eIF4E...
  17. pmc Impact of chronic alcohol ingestion on cardiac muscle protein expression
    Rachel L Fogle
    Department of Cellular and Molecular Physiology, Pennsylvania State University College of Medicine, Hershey, USA
    Alcohol Clin Exp Res 34:1226-34. 2010
    ..However, the full extent to which myocardial proteins are affected by chronic alcohol consumption remains unresolved...
  18. pmc Atypical antipsychotics rapidly and inappropriately switch peripheral fuel utilization to lipids, impairing metabolic flexibility in rodents
    Vance L Albaugh
    Department of Cellular and Molecular Physiology, Penn State College of Medicine, Hershey, PA 17033, USA
    Schizophr Bull 38:153-66. 2012
    ....
  19. ncbi Overexpression of ornithine decarboxylase decreases ventricular systolic function during induction of cardiac hypertrophy
    Emanuele Giordano
    Department of Cellular and Molecular Physiology, The Penn State College of Medicine, Hershey, PA 17033 2390, USA
    Amino Acids 42:507-18. 2012
    ..Since considerable variations in human cardiac polyamine and L-Arg content are likely, it is possible that alterations in these factors may influence myocyte contractility...