TNF- impairs heart and skeletal muscle protein synthesis by altering translation initiation

Lang, Charles H., Robert A. Frost, Angus C. Nairn, David A. MacLean, and Thomas C. Vary. TNFimpairs heart and skeletal muscle protein synthesis by altering translation initiation. Am J Physiol Endocrinol Metab 282: E336–E347, 2002. First published 2 October 2001; 10.1152/ ajpendo.00366.2001.—This study examined potential mechanisms contributing to the inhibition of protein synthesis in skeletal muscle and heart after administration of tumor necrosis factor (TNF). Rats had vascular catheters implanted, and TNFwas infused continuously for 24 h. TNFdecreased in vivo-determined rates of global protein synthesis in gastrocnemius (39%) and heart (25%). The TNF-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). TNFdecreased 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 or the content and phosphorylation state of eIF-2 . Skeletal muscle and heart from TNF-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 -form of 4E-BP1. In contrast, the infusion of TNFdid not alter the content of eEF-1 or eEF-2, or the phosphorylation state of eEF-2. In summary, these data suggest that TNFimpairs 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.