HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS		QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

This Article Full Text Full Text (PDF) All Versions of this Article: 287/5/C1482    most recent 00038.2004v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in Web of Science Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Web of Science (7) Citing Articles via Google Scholar Google Scholar Articles by Hong-Brown, L. Q. Articles by Lang, C. H. Search for Related Content PubMed PubMed Citation Articles by Hong-Brown, L. Q. Articles by Lang, C. H.

REPORT

Indinavir impairs protein synthesis and phosphorylations of MAPKs in mouse C₂C₁₂ myocytes

Department of Cellular and Molecular Physiology, Penn State University College of Medicine, Hershey, Pennsylvania 17033

Submitted 21 January 2004 ; accepted in final form 24 June 2004

ABSTRACT

Anti-retroviral therapy promotes clinical, immunologic, and virologic improvement in human immunodeficiency virus-infected patients. Whereas this therapy adversely affects carbohydrate and lipid metabolism, the effects of anti-retroviral drugs on muscle protein synthesis and degradation have not been reported. To examine these processes, we treated C₂C₁₂ myocytes with increasing concentrations of the protease inhibitor indinavir for 1 or 2 days. Treatment of myocytes with a therapeutic concentration of indinavir (20 µM) for 24 h decreased basal protein synthesis by 18%, whereas a 42% decline was observed after 48 h. A similar decrement, albeit quantitatively smaller, was detected with other protease inhibitors. Indinavir did not alter the rate of proteolysis. Likewise, indinavir did not impair the anabolic effect of insulin-like growth factor-I on protein synthesis. Mechanistically, indinavir decreased the phosphorylation of the S6 ribosomal protein (rpS6), and this reduction was associated with a decreased phosphorylation of p70S6 kinase and p90rsk as well as the upstream regulators ERK1/2 and MEK1/2. Indinavir also decreased the phosphorylation of Mnk1 and its upstream effectors, p38 MAPK and ERK1/2. Indinavir did not affect the phosphorylation of mTOR or 4E-BP1, but it did decrease the amount of the active eukaryotic initiation factor eIF4G-eIF4E complex. In conclusion, indinavir decreased protein synthesis in myocytes. This decrease was associated with the disruption of the ERK1/2 and p38 MAPK pathways and a reduction in both the level of functional eIF4F complex and rpS6 phosphorylation.

anti-retroviral drugs; mitogen-activated protein kinases; translation initiation

This article has been cited by other articles:

				M. Prod'homme, C. Rochon, M. Balage, H. Laurichesse, I. Tauveron, C. Champredon, P. Thieblot, J. Beytout, and J. Grizard Whole body leucine flux in HIV-infected patients treated with or without protease inhibitors Am J Physiol Endocrinol Metab, April 1, 2006; 290(4): E685 - E693. [Abstract] [Full Text] [PDF]

				L. Q. Hong-Brown, A. M. Pruznak, R. A. Frost, T. C. Vary, and C. H. Lang Indinavir alters regulators of protein anabolism and catabolism in skeletal muscle Am J Physiol Endocrinol Metab, September 1, 2005; 289(3): E382 - E390. [Abstract] [Full Text] [PDF]