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. ? ? ?

Agency
National Institute of Health (NIH)
Institute
National Institute on Alcohol Abuse and Alcoholism (NIAAA)
Type
Research Project (R01)
Project #
5R01AA012814-07
Application #
7275399
Study Section
Cardiac Contractility, Hypertrophy, and Failure Study Section (CCHF)
Program Officer
Gentry, Thomas
Project Start
2000-09-22
Project End
2011-08-31
Budget Start
2007-09-01
Budget End
2008-08-31
Support Year
7
Fiscal Year
2007
Total Cost
$302,284
Indirect Cost
Name
Pennsylvania State University
Department
Physiology
Type
Schools of Medicine
DUNS #
129348186
City
Hershey
State
PA
Country
United States
Zip Code
17033
Giordano, Emanuele; Hillary, Rebecca A; Vary, Thomas C et al. (2012) Overexpression of ornithine decarboxylase decreases ventricular systolic function during induction of cardiac hypertrophy. Amino Acids 42:507-518
Albaugh, Vance L; Vary, Thomas C; Ilkayeva, Olga et al. (2012) Atypical antipsychotics rapidly and inappropriately switch peripheral fuel utilization to lipids, impairing metabolic flexibility in rodents. Schizophr Bull 38:153-66
Fogle, Rachel L; Lynch, Christopher J; Palopoli, Mary et al. (2010) Impact of chronic alcohol ingestion on cardiac muscle protein expression. Alcohol Clin Exp Res 34:1226-34
Vary, Thomasc (2009) Oral leucine enhances myocardial protein synthesis in rats acutely administered ethanol. J Nutr 139:1439-44
Nairizi, Ali; She, Pengxiang; Vary, Thomas C et al. (2009) Leucine supplementation of drinking water does not alter susceptibility to diet-induced obesity in mice. J Nutr 139:715-9
Forsyth, Sara; Vary, Thomas C (2008) Partial dissociation of TSC2 and mTOR phosphorylation in cardiac and skeletal muscle of rats in vivo. Mol Cell Biochem 319:141-51
Pruznak, Anne M; Hong-Brown, Ly; Lantry, Rachel et al. (2008) Skeletal and cardiac myopathy in HIV-1 transgenic rats. Am J Physiol Endocrinol Metab 295:E964-73
Vary, Thomas C; Frost, Robert A; Lang, Charles H (2008) Acute alcohol intoxication increases atrogin-1 and MuRF1 mRNA without increasing proteolysis in skeletal muscle. Am J Physiol Regul Integr Comp Physiol 294:R1777-89
Vary, Thomas C; Lang, Charles H (2008) Differential phosphorylation of translation initiation regulators 4EBP1, S6k1, and Erk 1/2 following inhibition of alcohol metabolism in mouse heart. Cardiovasc Toxicol 8:23-32
Vary, Thomas C; Lang, Charles H (2008) Assessing effects of alcohol consumption on protein synthesis in striated muscles. Methods Mol Biol 447:343-55

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