TNF-α 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)-α. Rats had vascular catheters implanted, and TNF-α was infused continuously for 24 h. TNF-α decreased in vivo-determined rates of global protein synthesis in gastrocnemius (39%) and heart (25%). The TNF-α-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-α 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-2Bε or the content and phosphorylation state of eIF-2α. Skeletal muscle and heart from TNF-α-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 γ-form of 4E-BP1. In contrast, the infusion of TNF-α did not alter the content of eEF-1α or eEF-2, or the phosphorylation state of eEF-2. In summary, these data suggest that TNF-α 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.

Glucocorticoids and TNFα Interact Cooperatively to Mediate Sepsis-Induced Leucine Resistance in Skeletal Muscle

“…Finally, in a 3rd study, rats were injected via a lateral tail vein with L- [2,3,4,5,6-3 H]-phenylalanine (Phe; 150 mM, 30 μCi/mL; 1 mL/100 g body weight) 10 min after administration of leucine or saline for in vivo determination of muscle protein synthesis (15,19,20). Rats were then anesthetized with pentobarbital and the gastrocnemius was freeze-clamped 10 min after injection of Phe (i.e., 20 min after leucine).…”

“…In this study and all others, tissue and plasma samples were stored at -70°C until analyzed. Muscle was powdered and a portion used to estimate the rate of incorporation of [ 3 H]Phe into protein exactly as previously described (15,19,20).…”

“…The decreased muscle protein synthesis produced by acute peritonitis results from a defect in translation initiation characterized by the reduced constitutive phosphorylation of 4E-BP1 and S6K1/rpS6 (15). A reduction in peptide-chain initiation and protein synthesis is also observed in response to elevated tumor necrosis factor (TNF)-α and glucocorticoids, both of which are increased by sepsis (19)(20)(21)(22). Furthermore, sepsis and endotoxin impair the normal protein synthetic response to leucine (15,23).…”

Effect of tibiotarsal joint inflammation on gene expression and cross-sectional area in rat soleus muscle

“…In addition, neither TNF-alpha mRNA nor its protein content was altered in the inflammation group. TNF-alpha is a cytokine associated with muscle atrophy; it increases muscle proteolysis and inhibits skeletal muscle protein synthesis by altering the initiation of translation 22,38 . Therefore, our results indicate that sensitive markers of muscle atrophy analyzed in our study, at these time points, were not involved in the atrophy of the soleus muscle due to joint inflammation.…”

“…MAFbx (also known as atrogin-1) and Muscle Ring Finger-1 (MuRF1) [13][14][15][16] . Muscle fiber CSA reduction is also followed by changes in the regulation of genes related to muscle differentiation and growth (MyoD) 17,18 mass regulation (myostatin) 19 and proinflammatory factors, such as p38 Mitogen-Activated Protein Kinase (p38MAPK), Nuclear Factor kappa B-dependent (NFκB), and Tumour Necrosis Factoralpha (TNF-alpha) [20][21][22] . According to a previous study, the carrageenan injection increases TNF-alpha 23 , a cytokine able to increase the gene expression of MuRF1 and atrogin-1 in rat skeletal muscle 20,24,25 through the NFκB 20 and MAPK 25 pathways, respectively.…”