Indinavir alters regulators of protein anabolism and catabolism in skeletal muscle

Abstract

-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...

Alcohol and Indinavir Adversely Affect Protein Synthesis and Phosphorylation of MAPK and mTOR Signaling Pathways in C2C12 Myocytes

“…This finding is in agreement with previous cell culture and animals studies in which EtOH or Ind treatment decreased protein synthesis in skeletal, cardiac, and smooth muscle cells (Hong-Brown et al, 2004, 2005bPreedy et al, 1990;Reilly et al, 1997). In contrast, Janneh et al (2003) reported that Ind did not impair preadipocyte protein synthesis.…”

“…Paradoxically, treatment with HIV-protease inhibitors (PIs) as part of the highly active antiretroviral therapy (HAART) also causes metabolic disorders, even though HAART markedly reduces the morbidity and mortality in this patient population (Palella et al, 1998). Metabolic derangements associated with PI treatments include changes in protein metabolism, dyslipidemia, central adiposity, and peripheral lipodystrophy (Carr et al, 1998;Hong-Brown et al, 2005b). Likewise, several studies reported that PIs impair insulin-mediated glucose uptake by adipose and muscle tissues, resulting in a diabetic-like condition (Murata et al, 2000).…”

“…Likewise, several studies reported that PIs impair insulin-mediated glucose uptake by adipose and muscle tissues, resulting in a diabetic-like condition (Murata et al, 2000). Although mechanisms for the development of PI-associated lipid and carbohydrate abnormalities have been reported (Ben-Romano et al, 2003;Caron et al, 2001;Nolte et al, 2001), limited data are available concerning their effects on protein metabolism (Hong-Brown et al, 2005a, 2005b.…”

Acute alcohol intoxication increases atrogin-1 and MuRF1 mRNA without increasing proteolysis in skeletal muscle

“…Cells were cultured in Dulbecco's modified Eagle's medium containing 10% FBS, penicillin (100 units/ml), streptomycin (100 g/ml), and amphotericin (25 g/ml). Experiments were conducted using cells at the myotube stage in which 80 mM ethanol was added to cells, exactly as previously described (19,20). Cells were pulse-labeled with [ 35 S]-methionine/ cysteine in the presence or absence of alcohol for various times to determine the rate of degradation.…”

Skeletal and cardiac myopathy in HIV-1 transgenic rats

“…Furthermore, whereas the introduction of highly active antiretroviral therapy (HAART) has limited involuntary weight loss, a significant number of AIDS patients still manifest muscle wasting (46,56), especially as the severity of the disease progresses (5,53). However, investigation of the effects of HIV-1 infection under controlled conditions in humans is complicated by recurrent opportunistic bacterial infections and the pharmacological side effects of HAART, each of which can negatively impact muscle protein balance (15,24). Although the pathogenesis of HIV-induced wasting is multifactorial, where a reduction in energy intake and/or malabsorption is clearly contributory (12,30), the etiology of the metabolic defect is poorly characterized.…”