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

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AJP Regulatory Integrative and Comparative Physiology

Published online on

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 m) and aged (18 m) F344 rats were fed a nutritionally complete liquid diet containing alcohol (36% total calories) or an isocaloric isonitrogenous control diet for 20 wks. Cardiac structure and function, assessed by echocardiography, as well as myocardial protein synthesis and proteolysis did not differ in either alcohol- vs control-fed adult rats or in adult vs aged control-fed rats. In contrast, cardiac function was impaired in alcohol-fed aged rats, compared to age-matched control rats. Additionally, alcohol feeding decreased cardiac protein synthesis which was associated with decreased phosphorylation of 4E-BP1 and S6K1. This reduction in 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 MuRF1. These changes were associated with increased REDD1 and phosphorylation of AMPK, but no increase in AKT or FOXO3 phosphorylation. Finally, markers of autophagy (e.g., LC3B, Atg7, Atg12) and TNFα 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 to 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 pre-initiation complex and protein synthesis.