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HIV antiretroviral agents inhibit protein synthesis and decrease ribosomal protein S6 and 4EBP1 phosphorylation in
Ly Q Hong-Brown1, C Randell Brown, Charles H Lang
1Department of Cellular and Molecular Physiology (H166), Penn State University College of Medicine, Hershey, PA 17033, USA. lqh10@psu.edu
AIDS Research and Human Retroviruses
|October 18, 2005
Summary
Combined antiretroviral therapies improve AIDS outcomes but can disrupt metabolism. This study found that nelfinavir, nevirapine, and zidovudine reduce protein synthesis in skeletal muscle cells, impacting translation initiation.
Area of Science:
- Biochemistry
- Cell Biology
- Pharmacology
Background:
- Combined antiretroviral therapy (cART) significantly improves outcomes for patients with Acquired Immunodeficiency Syndrome (AIDS).
- cART is associated with metabolic complications, including dysregulation of lipid and carbohydrate metabolism.
- The impact of specific antiretroviral drugs on skeletal muscle protein synthesis remains an area of investigation.
Purpose of the Study:
- To investigate the effects of a protease inhibitor (nelfinavir), a nonnucleoside reverse transcriptase inhibitor (nevirapine), and a nucleoside reverse transcriptase inhibitor (zidovudine) on protein synthesis in skeletal muscle cells.
- To determine the impact of these drugs on key signaling pathways regulating translation initiation.
- To assess the interaction of these antiretroviral drugs with insulin signaling in muscle cells.
Main Methods:
- C2C12 myocytes were treated with varying concentrations of nelfinavir, nevirapine, or zidovudine for 24 or 48 hours.
- Protein synthesis rates were quantified by measuring [35S]methionine/cysteine incorporation.
- Western blotting was used to assess the phosphorylation status of ribosomal protein S6 (rpS6) and eukaryotic initiation factor 4E-binding protein 1 (4EBP1).
Main Results:
- Therapeutic concentrations of nelfinavir, nevirapine, and zidovudine significantly decreased protein synthesis in myocytes by 14-20% after 48 hours.
- Higher concentrations of nevirapine and nelfinavir induced an approximate 60% decline in protein synthesis.
- Zidovudine, but not nelfinavir or nevirapine, suppressed the insulin-stimulated increase in protein synthesis. Drug effects on protein synthesis correlated with reduced phosphorylation of rpS6 and/or 4EBP1.
Conclusions:
- Nelfinavir, nevirapine, and zidovudine treatments reduce protein synthesis in skeletal muscle cells.
- These inhibitory effects are linked to alterations in the phosphorylation of key proteins involved in translation initiation.
- Understanding these molecular mechanisms is crucial for managing metabolic complications associated with antiretroviral therapy.