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TNF-alpha impairs heart and skeletal muscle protein synthesis by altering translation initiation
Charles H Lang1, Robert A Frost, Angus C Nairn
1Department of Cellular and Molecular Physiology, The Pennsylvania State University College of Medicine, Hershey, Pennsylvania 17033, USA. clang@psu.edu
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.
Insights
Tumor necrosis factor-alpha (TNF-alpha) inhibits protein synthesis in skeletal muscle and heart by impairing translation initiation. This involves alterations in eukaryotic initiation factor 4E (eIF-4E) availability, reducing overall protein production.
Area of Science:
- Biochemistry
- Molecular Biology
- Physiology
Background:
- Tumor necrosis factor-alpha (TNF-alpha) is a pro-inflammatory cytokine implicated in various catabolic states.
- Protein synthesis is crucial for maintaining muscle and heart function.
- Understanding TNF-alpha's impact on protein synthesis is vital for managing related pathologies.
Purpose of the Study:
- To investigate the mechanisms by which TNF-alpha inhibits protein synthesis in skeletal muscle and heart.
- To identify specific molecular targets involved in TNF-alpha-induced protein synthesis suppression.
- To elucidate the role of translation initiation factors in this process.
Main Methods:
- Rats were infused with TNF-alpha for 24 hours via vascular catheters.
- In vivo protein synthesis rates were measured in gastrocnemius muscle and heart.
- Levels and activity of key eukaryotic initiation factors (eIFs) and elongation factors (eEFs) were assessed.
Main Results:
- TNF-alpha significantly decreased protein synthesis rates in gastrocnemius (39%) and heart (25%).
- Inhibition involved impaired translation initiation, specifically altered eIF-4E availability due to increased 4E-binding protein-1 (4E-BP1) binding.
- No significant changes were observed in elongation factors (eEF-1 alpha, eEF-2) or eIF-2B activity in the heart.
Conclusions:
- TNF-alpha impairs skeletal muscle and heart protein synthesis primarily by disrupting translation initiation.
- Alterations in eIF-4E availability, mediated by 4E-BP1, are a key mechanism for TNF-alpha-induced protein synthesis inhibition.
- These findings highlight potential therapeutic targets for conditions involving TNF-alpha-mediated muscle catabolism.