title: TNF-alpha impairs heart and skeletal muscle protein synthesis by altering translation initiation.
abstract: This study examined potential mechanisms contributing to the inhibition of protein synthesis in skeletal muscle and heart after administration of tumor necrosis factor (TNF)-alpha. Rats had vascular catheters implanted, and TNF-alpha was infused continuously for 24 h. TNF-alpha decreased in vivo-determined rates of global protein synthesis in gastrocnemius (39%) and heart (25%). The TNF-alpha-induced decrease in protein synthesis in the gastrocnemius involved a reduction in the synthesis of both myofibrillar and sarcoplasmic proteins. To identify potential mechanisms responsible for regulating mRNA translation, we examined several eukaryotic initiation factors (eIFs) and elongation factors (eEFs). TNF-alpha decreased the activity of eIF-2B in muscle (39%) but not in heart. This diminished activity was not caused by a reduction in the content of eIF-2B epsilon or the content and phosphorylation state of eIF-2 alpha. Skeletal muscle and heart from TNF-alpha-treated rats demonstrated 1) an increased binding of the translation repressor 4E-binding protein-1 (4E-BP1) with eIF-4E, 2) a decreased amount of eIF-4E associated with eIF-4G, and 3) a decreased content of the hyperphosphorylated gamma-form of 4E-BP1. In contrast, the infusion of TNF-alpha did not alter the content of eEF-1 alpha or eEF-2, or the phosphorylation state of eEF-2. In summary, these data suggest that TNF-alpha impairs skeletal muscle and heart protein synthesis, at least in part, by decreasing mRNA translational efficiency resulting from an impairment in translation initiation associated with alterations in eIF-4E availability.
authors.affiliation: Department of Cellular and Molecular Physiology, The Pennsylvania State University College of Medicine, Hershey, Pennsylvania 17033, USA. clang@psu.edu
authors.forename: Charles H
authors.initials: CH
authors.lastname: Lang
authors.forename: Robert A
authors.initials: RA
authors.lastname: Frost
authors.forename: Angus C
authors.initials: AC
authors.lastname: Nairn
authors.forename: David A
authors.initials: DA
authors.lastname: MacLean
authors.forename: Thomas C
authors.initials: TC
authors.lastname: Vary
mesh_terms: D000596:Amino Acids / Q000097:blood; D000818:Animals; D002352:Carrier Proteins / Q000378:metabolism; D015852:Eukaryotic Initiation Factor-2 / Q000378:metabolism; D020717:Eukaryotic Initiation Factor-2B / Q000378:metabolism; D039561:Eukaryotic Initiation Factor-4E; D006439:Hemodynamics / Q000187:drug effects; D006728:Hormones / Q000097:blood; D047908:Intracellular Signaling Peptides and Proteins; D008297:Male; D009124:Muscle Proteins / Q000037:antagonists & inhibitors* / Q000096:biosynthesis; D018482:Muscle, Skeletal / Q000378:metabolism*; D009206:Myocardium / Q000378:metabolism*; D010448:Peptide Initiation Factors / Q000378:metabolism; D010750:Phosphoproteins / Q000378:metabolism; D010766:Phosphorylation; D011132:Polyribosomes / Q000378:metabolism; D014176:Protein Biosynthesis / Q000187:drug effects* / Q000502:physiology; D051381:Rats; D017207:Rats, Sprague-Dawley; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology*
chemical_list: D000596:Amino Acids; D002352:Carrier Proteins; C499526:Eif4ebp1 protein, rat; D015852:Eukaryotic Initiation Factor-2; D020717:Eukaryotic Initiation Factor-2B; D039561:Eukaryotic Initiation Factor-4E; D006728:Hormones; D047908:Intracellular Signaling Peptides and Proteins; D009124:Muscle Proteins; D010448:Peptide Initiation Factors; D010750:Phosphoproteins; D014409:Tumor Necrosis Factor-alpha