-The HIV protease inhibitor indinavir adversely impairs carbohydrate and lipid metabolism, whereas its influence on protein metabolism under in vivo conditions remains unknown. The present study tested the hypothesis that indinavir also decreases basal protein synthesis and impairs the anabolic response to insulin in skeletal muscle. Indinavir was infused intravenously for 4 h into conscious rats, at which time the homeostasis model assessment of insulin resistance was increased. Indinavir decreased muscle protein synthesis by 30%, and this reduction was due to impaired translational efficiency. To identify potential mechanisms responsible for regulating mRNA translation, several eukaryotic initiation factors (eIFs) were examined. Under basal fasted conditions, there was a redistribution of eIF4E from the active eIF4E ⅐ eIF4G complex to the inactive eIF4E ⅐ 4E-BP1 complex, and this change was associated with a marked decrease in the phosphorylation of 4E-BP1 in muscle. Likewise, indinavir decreased constitutive phosphorylation of eIF4G and mTOR in muscle, but not S6K1 or the ribosomal protein S6. In contrast, the ability of a maximally stimulating dose of insulin to increase the phosphorylation of PKB, 4E-BP1, S6K1, or mTOR was not altered 20 min after intravenous injection. Indinavir increased mRNA expression of the ubiquitin ligase MuRF1, but the plasma concentration of 3-methylhistidine remained unaltered. These indinavir-induced changes were associated with a marked reduction in the plasma testosterone concentration but were independent of changes in plasma levels of IGF-I, corticosterone, TNF-␣, or IL-6. In conclusion, indinavir acutely impairs basal protein synthesis and translation initiation in skeletal muscle but, in contrast to muscle glucose uptake, does not impair insulin-stimulated signaling of protein synthetic pathways. eukaryotic initiation factor 4E; eukaryotic initiation factor 4E-binding protein-1; eukaryotic initiation factor 4G; mammalian target of rapamycin; ribosomal protein S6 kinase; muscle RING finger 1 UNTIL A CURE for human immunodeficiency virus (HIV) infection is found, antiretroviral therapy remains the first-line option for the treatment of this patient population. Highly active antiretroviral therapy (HAART) includes treatment with two kinds of reverse transcriptase inhibitors and an HIV protease inhibitor (11). This therapy decreases viral load and stimulates immune function, thereby prolonging survival of patients with AIDS. However, an increasing number of studies report that patients receiving HAART develop a variety of metabolic abnormalities (19). In particular, a majority of patients treated with the protease inhibitor indinavir develop insulin resistance (23, 44 -47, 51) characterized by diminished insulin-stimulated glucose uptake in adipose tissue and muscle (51). Protease inhibitors also adversely affect lipid metabolism, as exemplified by the elevated plasma concentrations of triglycerides and cholesterol as well as peripheral lipodystrophy and increased central adipo...