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

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Abstract

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 control-fed 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 RING-finger 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-α 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.

Original languageEnglish (US)
JournalAmerican Journal of Physiology - Regulatory Integrative and Comparative Physiology
Volume306
Issue number1
DOIs
StatePublished - Jan 1 2014

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Inbred F344 Rats
Alcohol Drinking
Alcohols
Proteins
Phosphorylation
Proteolysis
Transcription Factor 3
Raptors
Diet
Forkhead Transcription Factors
AMP-Activated Protein Kinases
Ubiquitin-Protein Ligases
Autophagy
Proteasome Endopeptidase Complex
Sirolimus
Fingers
DNA Damage
Echocardiography
Phosphotransferases
Muscles

All Science Journal Classification (ASJC) codes

  • Physiology
  • Physiology (medical)

Cite this

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title = "Chronic alcohol consumption disrupts myocardial protein balance and function in aged, but not adult, female F344 rats",
abstract = "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 control-fed 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 RING-finger 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-α 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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N2 - 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 control-fed 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 RING-finger 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-α 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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