Antiretroviral-Induced Defects in Muscle Protein Synthesis

Summary

Principal Investigator: Charles Lang
Abstract: HIV-1 protease inhibitors in general have a number of known effects on lipid and carbohydrate metabolism. Our data using both in vivo and in vitro model systems indicate that both indinavir and lopinavir also markedly decrease protein synthesis in skeletal muscle by impairing multiple steps in the control of mRNA translation. The long-term goal of this project is to elucidate the mechanisms by which lopinavir produces myopathy by altering muscle protein balance. The working hypothesis to be tested by the proposed research is that lopinavir antagonizes cell growth signaling systems, that include both eukaryotic initiation factor (elF) 4F and elF2/2B, under both basal conditions and in response to selected anabolic stimuli. Thus, lopinavir alters protein balance by impairing cap-dependent translational control and the formation of the 43S pre-initiation complex. Further, lopinavir adversely effects peptide-chain elongation. To address the questions implicit in our hypothesis, the proposed research has the following Specific Aims: (1) Elucidate the mechanism by which lopinavir impairs elF2B activity in skeletal muscle;(2) Determine whether alterations in the mTOR (mammalian target of rapamycin) nutrient signaling complex are responsible for lopinavir-induced alterations in 4E-BP1 phosphorylation;(3) Determine the mechanism by which lopinavir increases eukaryotic elongation factor (eEF)-2 phosphorylation and whether this change impairs peptide-chain elongation per se;(4) Elucidate the mechanism by which lopinavir impairs the normal anabolic response to nutritional signals (e.g., leucine) in muscle;and (5) Identify the biochemical loci mediating the potentiating effect of zidovudine (AZT) and lamivudine (3TC) on the lopinavir-induced decrease in protein synthesis. Complementary studies using both rats and cultured human myocytes will be used to elucidate the mechanism by which skeletal muscle translation efficiency is reduced by lopinavir, thereby leading to a more complete understanding of the metabolic disturbances produced by this HIV protease inhibitor alone and in combination with other antiretroviral agents. Such data is needed to both realize the full potential and avoid possible pitfalls of this drug in the long-term treatment of HIV-infected individuals.
Funding Period: ----------------2009 - ---------------2010-
more information: NIH RePORT

Top Publications

  1. ncbi Alcohol and indinavir adversely affect protein synthesis and phosphorylation of MAPK and mTOR signaling pathways in C2C12 myocytes
    Ly Q Hong-Brown
    Department of Cellular and Molecular Physiology H166, Penn State University College of Medicine, Hershey, Pennsylvania 17033, USA
    Alcohol Clin Exp Res 30:1297-307. 2006
  2. ncbi Alcohol regulates eukaryotic elongation factor 2 phosphorylation via an AMP-activated protein kinase-dependent mechanism in C2C12 skeletal myocytes
    Ly Q Hong-Brown
    Department of Cellular and Molecular Physiology, Penn State University College of Medicine, Hershey, Pennsylvania 17033, USA
    J Biol Chem 282:3702-12. 2007
  3. ncbi Protein kinase B/Akt: a nexus of growth factor and cytokine signaling in determining muscle mass
    Robert A Frost
    Department of Cellular and Molecular Physiology, The Penn State University College of Medicine, Hershey, PA 17033, USA
    J Appl Physiol (1985) 103:378-87. 2007
  4. pmc Chronic alcohol accentuates simian acquired immunodeficiency syndrome-associated wasting
    Patricia E Molina
    LSUHSC Department of Physiology and Alcohol Research Center, New Orleans, Louisiana 70112, USA
    Alcohol Clin Exp Res 32:138-47. 2008
  5. pmc Lopinavir impairs protein synthesis and induces eEF2 phosphorylation via the activation of AMP-activated protein kinase
    Ly Q Hong-Brown
    Department of Cellular and Molecular Physiology, Penn State University, College of Medicine, Hershey, Pennsylvania 17033, USA
    J Cell Biochem 105:814-23. 2008
  6. pmc Skeletal and cardiac myopathy in HIV-1 transgenic rats
    Anne M Pruznak
    Department of Cellular and Molecular Physiology, The Pennsylvania State University College of Medicine, Hershey, Pennsylvania 17033, USA
    Am J Physiol Endocrinol Metab 295:E964-73. 2008
  7. pmc Castration differentially alters basal and leucine-stimulated tissue protein synthesis in skeletal muscle and adipose tissue
    Qianning Jiao
    Cell and Molecular Physiology H166 Penn State College of Medicine, Hershey, PA 17033 0850, USA
    Am J Physiol Endocrinol Metab 297:E1222-32. 2009
  8. pmc Atypical antipsychotics rapidly and inappropriately switch peripheral fuel utilization to lipids, impairing metabolic flexibility in rodents
    Vance L Albaugh
    Department of Cellular and Molecular Physiology, Penn State College of Medicine, Hershey, PA 17033, USA
    Schizophr Bull 38:153-66. 2012
  9. pmc Disrupted anabolic and catabolic processes may contribute to alcohol-accentuated SAIDS-associated wasting
    Nicole J LeCapitaine
    Department of Physiology, Louisiana State University, Health Sciences Center, New Orleans, LA 70112, USA
    J Infect Dis 204:1246-55. 2011

Detail Information

Publications9

  1. ncbi Alcohol and indinavir adversely affect protein synthesis and phosphorylation of MAPK and mTOR signaling pathways in C2C12 myocytes
    Ly Q Hong-Brown
    Department of Cellular and Molecular Physiology H166, Penn State University College of Medicine, Hershey, Pennsylvania 17033, USA
    Alcohol Clin Exp Res 30:1297-307. 2006
    ..The goal of the present study was to identify signaling mechanisms responsible for the inhibitory effect of ethanol (EtOH) and Ind on protein synthesis...
  2. ncbi Alcohol regulates eukaryotic elongation factor 2 phosphorylation via an AMP-activated protein kinase-dependent mechanism in C2C12 skeletal myocytes
    Ly Q Hong-Brown
    Department of Cellular and Molecular Physiology, Penn State University College of Medicine, Hershey, Pennsylvania 17033, USA
    J Biol Chem 282:3702-12. 2007
    ..Collectively, the induction of eEF2 phosphorylation by EtOH is controlled by an increase in AMPK and a decrease in protein phosphatase 2A activity...
  3. ncbi Protein kinase B/Akt: a nexus of growth factor and cytokine signaling in determining muscle mass
    Robert A Frost
    Department of Cellular and Molecular Physiology, The Penn State University College of Medicine, Hershey, PA 17033, USA
    J Appl Physiol (1985) 103:378-87. 2007
    ..Activation of Akt stimulates muscle hypertrophy and antagonizes the loss of muscle protein. Here we review the many signals that funnel through Akt to alter muscle mass...
  4. pmc Chronic alcohol accentuates simian acquired immunodeficiency syndrome-associated wasting
    Patricia E Molina
    LSUHSC Department of Physiology and Alcohol Research Center, New Orleans, Louisiana 70112, USA
    Alcohol Clin Exp Res 32:138-47. 2008
    ..We hypothesized that alcohol-induced loss in lean body mass is likely to exacerbate the AIDS wasting syndrome, particularly at the terminal stage of AIDS (SAIDS)...
  5. pmc Lopinavir impairs protein synthesis and induces eEF2 phosphorylation via the activation of AMP-activated protein kinase
    Ly Q Hong-Brown
    Department of Cellular and Molecular Physiology, Penn State University, College of Medicine, Hershey, Pennsylvania 17033, USA
    J Cell Biochem 105:814-23. 2008
    ..Collectively, these results indicate that LPV decreases protein synthesis, at least in part, via inhibition of eEF2. This appears regulated by AMPK which can act directly on eEF2 or indirectly via the action of eEF2K...
  6. pmc Skeletal and cardiac myopathy in HIV-1 transgenic rats
    Anne M Pruznak
    Department of Cellular and Molecular Physiology, The Pennsylvania State University College of Medicine, Hershey, Pennsylvania 17033, USA
    Am J Physiol Endocrinol Metab 295:E964-73. 2008
    ..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 insulin-like growth factor I...
  7. pmc Castration differentially alters basal and leucine-stimulated tissue protein synthesis in skeletal muscle and adipose tissue
    Qianning Jiao
    Cell and Molecular Physiology H166 Penn State College of Medicine, Hershey, PA 17033 0850, USA
    Am J Physiol Endocrinol Metab 297:E1222-32. 2009
    ....
  8. pmc Atypical antipsychotics rapidly and inappropriately switch peripheral fuel utilization to lipids, impairing metabolic flexibility in rodents
    Vance L Albaugh
    Department of Cellular and Molecular Physiology, Penn State College of Medicine, Hershey, PA 17033, USA
    Schizophr Bull 38:153-66. 2012
    ....
  9. pmc Disrupted anabolic and catabolic processes may contribute to alcohol-accentuated SAIDS-associated wasting
    Nicole J LeCapitaine
    Department of Physiology, Louisiana State University, Health Sciences Center, New Orleans, LA 70112, USA
    J Infect Dis 204:1246-55. 2011
    ..The purpose of this study was to investigate changes in pathways that may contribute to muscle wasting in chronic binge alcohol-fed SIV-infected macaques...