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TNF-alpha impairs heart and skeletal muscle protein synthesis by altering translation initiation.
- Source :
-
American journal of physiology. Endocrinology and metabolism [Am J Physiol Endocrinol Metab] 2002 Feb; Vol. 282 (2), pp. E336-47. - Publication Year :
- 2002
-
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.
- Subjects :
- Amino Acids blood
Animals
Carrier Proteins metabolism
Eukaryotic Initiation Factor-2 metabolism
Eukaryotic Initiation Factor-2B metabolism
Eukaryotic Initiation Factor-4E
Hemodynamics drug effects
Hormones blood
Intracellular Signaling Peptides and Proteins
Male
Muscle Proteins biosynthesis
Peptide Initiation Factors metabolism
Phosphoproteins metabolism
Phosphorylation
Polyribosomes metabolism
Protein Biosynthesis physiology
Rats
Rats, Sprague-Dawley
Muscle Proteins antagonists & inhibitors
Muscle, Skeletal metabolism
Myocardium metabolism
Protein Biosynthesis drug effects
Tumor Necrosis Factor-alpha pharmacology
Subjects
Details
- Language :
- English
- ISSN :
- 0193-1849
- Volume :
- 282
- Issue :
- 2
- Database :
- MEDLINE
- Journal :
- American journal of physiology. Endocrinology and metabolism
- Publication Type :
- Academic Journal
- Accession number :
- 11788365
- Full Text :
- https://doi.org/10.1152/ajpendo.00366.2001