Human immunodeficiency virus (HIV)-1 infection in humans leads to the erosion of lean body mass (LBM) the mechanism of which is poorly defined. Therefore, the purpose of the present study was to determine whether transgenic (Tg) rats which constitutively over express HIV-1 viral proteins exhibit muscle wasting and to elucidate putative mechanisms. Over 7 months, Tg rats gained less body weight than pair-fed control rats and this resulted exclusively from a proportional reduction in lean, not fat, mass. Both fast- and slow-twitch muscles exhibited atrophy in Tg rats which 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 were elevated in gastrocnemius of Tg rats suggesting increased muscle proteolysis. Likewise, 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. Further, 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 IGF-I was reduced in Tg rats. Although hepatic injury was implicated by increased plasma levels of AST and ALT, 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 IGF-I.