Inflammation-mediated muscle metabolic dysregulation local and remote to the site of major abdominal surgery

Abstract

Background & aims: Postoperative hyperglycaemia is common in patients having major surgery and is associated with adverse outcomes. This study aimed to determine whether bacteraemia contributed to postoperative systemic inflammation, and whether increases in the expression of muscle mRNAs and proteins reflecting increased muscle inflammation, atrophy and impaired carbohydrate oxidation were evident at the time of surgery, and both local and distant to the site of trauma, and could be associated with impaired glucoregulation.

Methods: Fifteen adult patients without diabetes undergoing major abdominal surgery participated in this observational study set in a university teaching hospital. Arterialised-venous blood samples and muscle biopsies were obtained before and after major elective abdominal surgery, from sites local (rectus abdominis - RA) and remote to the site of surgery (vastus lateralis - VL). The main outcome measures included blood glucose concentrations, gut permeability and changes in expression of muscle mRNAs and proteins linked to inflammation and glucose regulation.

Results: Immediately postoperatively, RA demonstrated markedly increased mRNA expression levels of cathepsin-L (7.5-fold, P < 0.05), FOXO1 (10.5-fold, P < 0.05), MAFbx (11.5-fold, P < 0.01), PDK4 (7.8-fold, P < 0.05), TNF-α (16.5-fold, P < 0.05) and IL-6 (1058-fold, P < 0.001). A similar, albeit blunted, response was observed in VL. Surgery also increased expression of proteins linked to inflammation (IL-6; 6-fold, P < 0.01), protein degradation (MAFbx; 4.5-fold, P < 0.5), and blunted carbohydrate oxidation (PDK4; 4-fold, P < 0.05) in RA but not VL. Increased systemic inflammation (TNF-α, P < 0.05; IL-6, P < 0.001), and impaired postoperative glucose tolerance (P < 0.001), but not bacteraemia (although gut permeability was increased significantly, P < 0.05) or increased plasma cortisol, were noted 48 h postoperatively.

Conclusions: A systemic postoperative proinflammatory response was accompanied by muscle inflammation and metabolic dysregulation both local and remote to the site of surgery, and was not accompanied by bacteraemia.

Clinical trial registration: Registered at http://clinicaltrials.gov (NCT01134809).

Keywords: Abdominal surgery; Cytokines; Gene expression; Metabolic response; Muscle inflammatory responses; Postoperative hyperglycaemia.

Fig. 1

A. Gut permeability in participants undergoing major abdominal surgery preoperatively and 48 h postoperatively (n = 15), *P < 0.05. B. The presence of DNA representative of Gram positive bacteria in circulating blood in participants 48 h postoperatively (n = 15). The positive control comprised of DNA isolated from the Gram positive wild-type strain SG38 of Bacillus subtilis, which is found in the gastrointestinal tract of humans.

Fig. 2

Fold change in (top) Akt1, Cathepsin-L (CSTL1), FOXO1, MAFbx, myostatin (MSTN), PDK4, TNF-α and IRS1 mRNA expression and (bottom) IL-6 mRNA expression in rectus abdominis (local to the site of surgery) and vastus lateralis (distant from the site of surgery site) muscle obtained at the start of surgery and immediately after surgery from participants undergoing major abdominal surgery (n = 15). Values are expressed as fold changes from the value at the start of surgery. *P < 0.05, **P < 0.01, ***P < 0.001, significantly different from the value at the start of surgery.

Fig. 3

Relative protein expression levels of IL-6, MAFbx, PDK4, the ratio of Pp70S6K/p70S6K and the ratio of PFOXO1/FOXO1 in (top) rectus abdominis muscle (local to the site of surgery) and (bottom) vastus lateralis muscle (distant from the site of surgery) obtained at the start of surgery and immediately after surgery from participants undergoing major abdominal surgery (n = 15). Values are expressed as fold change from the value at the start of surgery. *P < 0.05, **P < 0.01 significantly different from the value at the start of surgery (set at 1).