Thermal injury impairs cardiac protein synthesis and is associated with alterations in translation initiation

Abstract

The purpose of the present study was to determine whether burn injury decreases myocardial protein synthesis and potential contributing mechanisms for this impairment. To address this aim, thermal injury was produced by a 40% total body surface area full-thickness scald burn in anesthetized rats, and the animals were studied 24 h late. Burn decreased the in vivo-determined rate of myocardial protein synthesis and translation efficiency by 25% but did not alter the protein synthetic rate in skeletal muscle. To identify potential mechanisms responsible for regulating mRNA translation in cardiac muscle, we examined several eukaryotic initiation factors (eIFs) and elongation factors (eEFs). Burn failed to alter eIF2B activity or the total amount or phosphorylation status of either eIF2 alpha or eIF2B epsilon in heart. In contrast, hearts from burned rats demonstrated 1) an increased binding of the translational repressor 4E-BP1 with eIF4E, 2) a decreased amount of eIF4E associated with eIF4G, and 3) a decreased amount of the hyperphosphorylated gamma-form of 4E-BP1. These changes in eIF4E availability were not seen in gastrocnemius muscle where burn injury did not decrease protein synthesis. Furthermore, constitutive phosphorylation of mTOR, S6K1, the ribosomal protein S6, and eIF4G were also decreased in hearts from burned rats. Burn did not appear to adversely affect elongation because there was no significant difference in the myocardial content of eEF1 alpha or eEF2 or the phosphorylation state of eEF2. The above-mentioned burn-induced changes in mRNA translation were associated with an impairment of in vitro myocardial performance. Finally, 24 h postburn, the cardiac mRNA content of IL-1 beta, IL-6, and high-mobility group protein B1 (but not TNF-alpha) was increased. In summary, these data suggest that thermal injury specifically decreases cardiac protein synthesis in part by decreasing mRNA translation efficiency resulting from an impairment in translation initiation associated with alterations in eIF4E availability and S6K1 activity.

Leucine Acutely Reverses Burn-Induced Alterations in Translation Initiation in Heart

“…Data from previous studies indicate that the total ribosome number in heart was unchanged 24 h after burn injury (7). However, burn did decrease translational efficiency in cardiac tissue at this time point.…”

“…Despite the uncertainty of the exact underlying mechanism, the burn-induced decrease in cardiac contractility is associated with a loss of the myofibrillar proteins actin and myosin (6). Furthermore, we have previously demonstrated a marked decrease in cardiac protein synthesis 24 h after thermal injury and that this defect is associated with a concomitant reduction in myocardial function (7). This burn-induced decrease in myocardial protein synthesis appears relatively tissue specific because a reduction in the synthetic rate was not observed in either skeletal muscle or liver.…”

Skeletal muscle cytokines: regulation by pathogen-associated molecules and catabolic hormones

“…HMGB-1, receptor for advanced glycation endproducts, TLR-2, and TLR-4 mRNA are all found in both tissues [8, 35,36]. HMGB-1 may stimulate the local synthesis of TNF or other cytokines within muscle much as it does in inflammatory cells.…”

Rapamycin blunts nutrient stimulation of eIF4G, but not PKCε phosphorylation, in skeletal muscle

“…Likewise, enhanced phosphorylation of eIF4G correlated with stimulation of protein synthesis and assembly of the eIF4G⅐eIF4E complex following perfusion of hindlimb muscle with buffer supplemented with leucine (5,42). On the other hand, thermal injury reduces the phosphorylation of eIF4G and assembly of eIF4E⅐eIF4G complex in heart (20). Hence, phosphorylation of eIF4G is a potentially important mechanism controlling protein synthesis through assembly of the eIF4G⅐eIF4E complex in striated muscle.…”