Muscle protein catabolism and splanchnic arginine consumption drive arginine dysregulation during Pseudomonas aeruginosa-induced early acute sepsis in swine.

Human sepsis is characterized by increased protein breakdown and changes in arginine and citrulline metabolism. However, it is unclear whether this is caused by changes in transorgan metabolism. We therefore studied the changes in protein and arginine-related metabolism on the whole body (Wb) and transorgan levels in a Pseudomonas aeruginosa-induced pig sepsis model. We studied 22 conscious pigs for 18 h during sepsis induced by infusing live bacteria (Pseudomonas aeruginosa) or after placebo infusion (Control). We used stable isotope tracers to measure Wb and skeletal muscle protein synthesis and breakdown, as well as Wb, splanchnic, skeletal muscle, hepatic, and portal-drained viscera (PDV) arginine and citrulline disposal and production rates. During sepsis, arginine Wb production (P = 0.0146), skeletal muscle release (P = 0.0035), and liver arginine uptake were elevated (P = 0.0031). Wb de novo arginine synthesis, citrulline production, and transorgan PDV release of citrulline, glutamine, and arginine did not differ between Sepsis and Control pigs. However, Wb (P < 0.0001) and muscle (P < 0.001) protein breakdown were increased, suggesting that the enhanced arginine production is predominantly derived from muscle breakdown in sepsis. In conclusion, live bacterium sepsis increases muscle arginine release and liver uptake, mirroring previous pig endotoxemia studies. In contrast to observations in humans, acute live bacterium sepsis in pigs does not change citrulline production or arterial arginine concentration. We therefore conclude that the arginine dysregulation observed in human sepsis is possibly initiated by enhanced protein catabolism and splanchnic arginine catabolism, whereas decreased arterial arginine concentration and citrulline metabolism may require more time to fully manifest in patients. NEW & NOTEWORTHY: Our work highlights that arginine availability may be largely determined by muscle breakdown and hepatic extraction in early sepsis, while citrulline production appears maintained. Additionally, our work highlights a novel ANCOVA approach for transorgan analysis to control for inherent variation in transorgan data and increase statistical sensitivity. [ABSTRACT FROM AUTHOR]