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

Abstract

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.

Alcoholic Cardiomyopathy: Pathophysiologic Insights

“…Interestingly, activation of mTOR leads to inhibition of autophagy. As noted above, chronic alcohol exposure leads to a decrease in mTOR activity, which corresponds to increased markers of autophagy (65). Furthermore, the autophagy pathway is rapidly upregulated during ATP depletion, mitochondrial dysfunction, and oxidative stress.…”

“…Ethanol-induced decreases in myocardial protein synthesis may be mediated in part by decreases in mammalian (or mechanistic) target of rapamycin (mTOR) activity (63–65). mTOR is a kinase that regulates cell growth, cell proliferation, cell motility, cell survival, protein synthesis, and transcription (66).…”

“…In skeletal muscle, ubiquitin E3 ligases, such as atrogin-1 and muscle RING Finger 1 (MuRF1), accelerate protein breakdown and lead to muscle atrophy (67,68). Recently, Lang and Korzick (65) reported that 20 weeks of alcohol consumption in female Fischer 344 rats increased myocardial atrogin-1 and MuRF1 expression (e.g., messenger ribonucleic acid levels). In this same study, investigators found increased markers of autophagy, such as LC3B and autophagy-related gene 7 proteins and tumor necrosis factor α, along with a reduction in mTOR activity.…”

REDD1 attenuates cardiac hypertrophy via enhancing autophagy

“…It functions as an inhibitor of mTOR which regulates cell growth and metabolism. In cardiovascular field, studies about the role of REDD1 limit in how the expression of REDD1 reacts in different settings including acute and chronic alcohol consumption [5,6], diet-induced obesity [21] and ischemia/reperfusion injury [7]. However, the role of REDD1 in pathological cardiac hypertrophy and the related mechanisms remain unknown.…”

“…REDD1 is identified to function as an inhibitor of mTOR and thereby exerts its biological influence tightly related to the inhibition of mTOR in different settings. In cardiovascular field, REDD1 expression in heart increased in acute alcohol intoxication [5]; decreased cardiac protein synthesis caused by chronic alcohol consumption was associated with inactivation of mTOR mediated by increased REDD1 expression [6]. Moreover, REDD1 is one of the proteins that modulate mTOR activity when the heart underwent ischemia/reperfusion (I/R) injury [7].…”