Chronic ethanol consumption does not alter the distribution of mTOR between TORC1 and TORC2, but instead diminishes mTOR phosphorylation on Ser(2448) independent of changes in tumor suppressor complex 2 and PKB phosphorylation. Furthermore, the data suggest that protein synthesis in rats fed a diet containing ethanol is limited by mTOR-dependent reduction in phosphorylation of S6K1(Thr(389)) and eIF4G(Ser(1108)) secondary to reduced phosphorylation of mTOR(Ser(2448)).

The mechanism by which human immunodeficiency virus (HIV)-1 infection in humans leads to the erosion of lean body mass is poorly defined. Therefore, the purpose of the present study was to determine whether transgenic (Tg) rats that constitutively overexpress HIV-1 viral proteins exhibit muscle wasting and to elucidate putative mechanisms. Over 7 mo, Tg rats gained less body weight than pair-fed controls exclusively as a result of a proportional reduction in lean, not fat, mass. Fast- and slow-twitch muscle atrophy in Tg rats did not result from a reduction in the in vivo-determined rate of protein synthesis. In contrast, urinary excretion of 3-methylhistidine, as well as the content of atrogin-1 and the 14-kDa actin fragment, was elevated in gastrocnemius of Tg rats, suggesting increased muscle proteolysis. Similarly, Tg rats had reduced cardiac mass, which was independent of a change in protein synthesis. This decreased cardiac mass was associated with a reduction in stroke volume, but cardiac output was maintained by a compensatory increase in heart rate. The HIV-induced muscle atrophy was associated with increased whole body energy expenditure, which was not due to an elevated body temperature or secondary bacterial infection. Furthermore, the atrophic response could not be attributed to the development of insulin resistance, decreased levels of circulating amino acids, or increased tissue cytokines. However, skeletal muscle and, to a lesser extent, circulating insulin-like growth factor I was reduced in Tg rats. Although hepatic injury was implicated by increased plasma levels of aspartate and alanine aminotransferases, hepatic protein synthesis was not different between control and Tg rats. 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.

Heavy, chronic alcohol consumption is associated with a syndrome known as alcoholic heart muscle disease (AHMD), clinically characterized by ventricular dilation, thinning of the ventricular wall, and myocardial dysfunction. These changes occur as a result of a decreased rate of protein synthesis. The clinical manifestations of AHMD are consistent with alterations in structural and myofibrillar proteins. The current study used a proteomic approach with isotope coded affinity tag (ICAT) labeling and mass spectrometry to delineate changes in protein expression in a chronic (16 wk) alcohol rat model. Chronic alcohol ingestion was associated with falls in mitochondrial proteins associated with TCA cycle (citrate synthase, isocitrate dehydrogenase, succinyl‐CoA synthetase, malate dehydrogenase) as well as enzymes involved in electron transport (ubiquinone, adenine nucleotide translocator, F1‐ATPase, H+ transporting two‐sector ATPase) and energy transfer (nucleoside‐diphosphate kinase, creatine kinase). No changes were seen in pyruvate dehydrogenase complex, NADH coenzyme Q reductase, or ubiquinol cytochrome c reductase. The results indicate myocardial mitochondrial proteins are adversely affected in chronic alcoholism. (PHS; RO1 AA012814).