Post‐burn Regulation of Cardiac Protein Synthesis and Degradation by IL‐6
Authors: El Ayadi Amina , Guillory Ashley , Prasai Anesh , Wang Ye , Porter Craig , Herndon David N , Finnerty Celeste C 
Published: November 2023

Burn injury induces a hypermetabolic response that is characterized by increased catecholamine and systemic inflammatory cytokines for up to 3 years post‐burn. Burn injury is associated with cardiac dysfunction and complications in respiration that may be due to a failure of respiratory muscles to function properly. Among the respiratory muscles, the heart and the diaphragm play an important role in the pathophysiological mechanisms that lead to difficulty in weaning patients from mechanical ventilation. Previous studies have shown that prolonged mechanical ventilation can stimulate muscle proteolysis. We have reported that burn injury alters the beta‐adrenergic signaling in the heart at 7 days post‐burn and shown that the IL‐6 JAK/Stat pathway is activated in the diaphragm post‐burn. To decipher the role of this pathway in proteostasis following burn injury, we used the IL‐6 knockout (IL‐6 KO) mice that had undergone a 25% TBSA burn and analyzed the protein levels of various components of the ubiquitin‐proteasome pathway known to play an important role in degradation and turnover of various heart muscle proteins. We found that total protein ubiquitination was significantly upregulated in the wild type (WT) mice following burn injury (p<0.05). Basal protein ubiquitination was significantly higher in the IL‐6 KO compared to WT mice (P<0.001). In addition, ubiquitinated proteins were significantly upregulated in the IL‐6 KO compared to WT mice in response to burn injury (p<0.001). The basal levels of the proteasome subunit S5a, known to recognize ubiquitinated protein and to target them to the proteasome for degradation, were significantly higher in the IL‐6 KO compared to WT mice (P<0.0001). The levels of S5a were significantly elevated in response to burn in the IL‐6 KO compared to WT mice (P<0.001). The basal levels of the substrate recognition component of the (SKP1‐CUL1‐F‐box protein) E3 ubiquitin‐protein ligase complex (FBX32) showed a significant increase in the IL‐6 KO control compared to WT controls (p<0.05). These levels were significantly up‐regulated in repose to burn injury in the IL‐6 KO compared to WT mice (p<0.05). The basal levels of the protein synthesis regulator p‐70S6k were significantly lower in the IL‐6 KO compared to WT mice (p<0.05). These levels were further decreased in the IL‐6 KO post‐burn compared to IL‐6 KO control (p<0.001) and WT burned mice (p<0.001). These results suggest a role for the IL‐6 pathway in the regulation of protein degradation and protein synthesis post‐burn.Support or Funding InformationThis study was supported by grants from the National Institute of Health (P50‐GM60338, R01‐GM56687, and T32‐GM8256, NIH R01 GM 112936‐01), Shriners Hospitals for Children (71008, 71001, 84202 and 84080), and the Shriners Hospital for Children fellowship for AE (SHC 84202). This study was conducted with the support of the Institute for Translational Sciences at the University of Texas Medical Branch, supported in part by a Clinical and Translational Science Award (UL1TR000071) from the National Center for Advancing Translational Sciences, National Institutes of Health