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. 2023 Jul 5;27(1):266.
doi: 10.1186/s13054-023-04551-1.

Moderate exercise-induced dynamics on key sepsis-associated signaling pathways in the liver

Hari Prasad Osuru  1 , Keita Ikeda  2 , Navya Atluri  2 , Robert H Thiele  3
Affiliations

Moderate exercise-induced dynamics on key sepsis-associated signaling pathways in the liver

Hari Prasad Osuru et al. Crit Care. .

Abstract

Background: There is a clear relationship between quantitative measures of fitness (e.g., VO2 max) and outcomes after surgical procedures. Whether or not fitness is a modifiable risk factor and what underlying biological processes drive these changes are not known. The purpose of this study was to evaluate the moderate exercise training effect on sepsis outcomes (survival) as well as the hepatic biological response. We chose to study the liver because it plays a central role in the regulation of immune defense during systemic infection and receives blood flow directly from the origin of infection (gut) in the cecal ligation and puncture (CLP) model.

Methods: We randomized 50 male (♂) and female (♀) Sprague-Dawley rats (10 weeks, 340 g) to 3 weeks of treadmill exercise training, performed CLP to induce polymicrobial "sepsis," and monitored survival for five days (Part I). In parallel (Part II), we randomized 60 rats to control/sedentary (G1), exercise (G2), exercise + sham surgery (G3), CLP/sepsis (G4), exercise + CLP [12 h (G5) and 24 h (G6)], euthanized at 12 or 24 h, and explored molecular pathways related to exercise and sepsis survival in hepatic tissue and serum.

Results: Three weeks of exercise training significantly increased rat survival following CLP (polymicrobial sepsis). CLP increased inflammatory markers (e.g., TNF-a, IL-6), which were attenuated by exercise. Sepsis suppressed the SOD and Nrf2 expression, and exercise before sepsis restored SOD and Nrf2 levels near the baseline. CLP led to increased HIF1a expression and oxidative and nitrosative stress, the latter of which were attenuated by exercise. Haptoglobin expression levels were increased in CLP animals, which was significantly amplified in exercise + CLP (24 h) rats.

Conclusions: Moderate exercise training (3 weeks) increased the survival in rats exposed to CLP, which was associated with less inflammation, less oxidative and nitrosative stress, and activation of antioxidant defense pathways.

Keywords: CLP; Exercise training; Liver injury; Sepsis-hub genes; Sepsis-survival.

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Conflict of interest statement

Dr. Thiele performs consulting work on advanced monitoring technology for Medtronic, Edwards LifeSciences, and Philips Medical. Dr. Thiele received an investigator-initiated award from Apple to explore the use of exercise training in patients undergoing cancer surgery. Dr. Thiele has an NIH Grant (R-21, NIBIB) to develop near-infrared spectroscopy equipment to measure the oxidation state of cytochrome aa3 non-invasively. The other authors declare that they have no competing interests.

Figures

Fig. 1
Fig. 1
Overall experimental plan of Part I, sepsis survival and Part II, biochemical mechanisms and response pathways analysis
Fig. 2
Fig. 2
Survival curves for rats exposed to CLP with and without exercise preconditioning. A Survival curves for all animals ♂ and ♀ rats; P = 0.0132; n = 48, B Survival curves for ♂ rats only; P = 0.3206; n = 24 and C Survival curves for ♀ rats only; P = 0.0288; n = 24
Fig. 3
Fig. 3
mRNA expression in males (top) and females (bottom) stratified by group. G1 = sedentary, G2 = exercise-trained, G3 = exercise trained + sham surgery, G4 = CLP (untrained, tissue harvest at 24 h), G5 = CLP (trained, tissue harvest at 12 h), G6 = CLP (trained, tissue harvest at 24 h) The red dashed line represents the control group fold change level (FC = 1)
Fig. 4
Fig. 4
A–F, protein expression of antioxidant agents in males (L) and females (R) stratified by group. G, Western Blots H, Compiled quantification data (A–F). G1 = sedentary, G2 = exercise-trained, G3 = exercise trained + sham surgery, G4 = CLP (untrained, tissue harvest at 24 h), G5 = CLP (trained, tissue harvest at 12 h), G6 = CLP (trained, tissue harvest at 24 h)
Fig. 5
Fig. 5
A–D protein expression of anti-inflammatory markers and E lactate level in males (L) and females (R) stratified by group. F, Western Blots G, Compiled quantification data (A–E). G1 = sedentary, G2 = exercise-trained, G3 = exercise trained + sham surgery, G4 = CLP (untrained, tissue harvest at 24 h), G5 = CLP (trained, tissue harvest at 12 h), G6 = CLP (trained, tissue harvest at 24 h)
Fig. 6
Fig. 6
A–E, protein expression of proteins involved in the metabolic response to stress in males (L) and females (R) stratified by group. F, Western Blots G, Compiled quantification data (A–E). G1 = sedentary, G2 = exercise-trained, G3 = exercise trained + sham surgery, G4 = CLP (untrained, tissue harvest at 24 h), G5 = CLP (trained, tissue harvest at 12 h), G6 = CLP (trained, tissue harvest at 24 h)
Fig. 7
Fig. 7
Sepsis increases the Hif1a-signaling target proteins (mTOR, AKT, AMPK, PRKG1, and PDE5a) expression levels in liver tissue, pre-exercise training attenuates this response. A–E, HIF-1α target proteins in males (L) and females (R) stratified by group. F, Western Blots G, compiled quantification data (A–E). G1 = sedentary, G2 = exercise-trained, G3 = exercise trained + sham surgery, G4 = CLP (untrained, tissue harvest at 24 h), G5 = CLP (trained, tissue harvest at 12 h), G6 = CLP (trained, tissue harvest at 24 h)
Fig. 8
Fig. 8
A–E, protein expression of NRF-2 signaling proteins in males (L) and females (R) stratified by group. F, Western Blots G, Compiled quantification data (A–E). G1 = sedentary, G2 = exercise-trained, G3 = exercise trained + sham surgery, G4 = CLP (untrained, tissue harvest at 24 h), G5 = CLP (trained, tissue harvest at 12 h), G6 = CLP (trained, tissue harvest at 24 h)
Fig. 9
Fig. 9
A–E, protein expression of proteins involved in the metabolic response to stress in males (L) and females (R) stratified by group. F, Western Blots G, Compiled quantification data (A–E). G1 = sedentary, G2 = exercise-trained, G3 = exercise trained + sham surgery, G4 = CLP (untrained, tissue harvest at 24 h), G5 = CLP (trained, tissue harvest at 12 h), G6 = CLP (trained, tissue harvest at 24 h)
Fig. 10
Fig. 10
Sepsis increase the stress marker HP, cf-HB, PC, and NO levels in serum and liver tissue, Pre-exercise training controlled these stress marker levels both in male and female sepsis animals at post-operative hours 12 and 24. A Haptoglobin (HP) protein expression levels in the Liver, B Cell-free Hemoglobin (cf-HB) levels in serum, C Protein carbonyl (PC) content and D Nitric Oxide (NO) levels in Liver homogenate, E Western blotting images showing the protein densities of HP, and loading control β-tubulin in the Liver tissue G The graph showing the compiled data (A–D). G1 = sedentary, G2 = exercise-trained, G3 = exercise trained + sham surgery, G4 = CLP (untrained, tissue harvest at 24 h), G5 = CLP (trained, tissue harvest at 12 h), G6 = CLP (trained, tissue harvest at 24 h)
Fig. 11
Fig. 11
Sepsis increases the accumulation of nitrotyrosine (NT) protein adducts (peroxynitrite formation) in the Liver, Pre-exercise training attenuates these adducts levels. Enlarged part of the liver showing both central vein (CV) and portal vein (PV) tissue morphology. Male (A) and Female (B) rat liver sections show Hematoxylin–eosin (H&E) staining and nitrotyrosine (NT) protein adducts Immunostaining (brown stain cells marked with black arrowhead). H&E staining of the liver tissue sections showed extensive liver damage and inflammatory cell infiltration. Graph (C; ♂, n = 3) and (D; ♀,n = 3) represents the NT protein adducts (positive cells) density (μm−2) in the Liver tissue sections. G1 = sedentary, G2 = exercise-trained, G3 = exercise trained + sham surgery, G4 = CLP (untrained, tissue harvest at 24 h), G5 = CLP (trained, tissue harvest at 12 h), G6 = CLP (trained, tissue harvest at 24 h). Images scale bar = 90 μm
Fig. 12
Fig. 12
A quantified S-nitrosylation in ♂ and ♀ stratified by group. B representative gels depicting total S-nitrosylated protein (upper) and loading control total protein in ponceau S (lower). C quantified GSNOR protein levels, and representative western blot images D S-nitrosylation and GSNOR (indirectly regulates NO signaling associated with protein S-nitrosylation) levels displayed simultaneously. G1 = sedentary, G2 = exercise-trained, G3 = exercise trained + sham surgery, G4 = CLP (untrained, tissue harvest at 24 h), G5 = CLP (trained, tissue harvest at 12 h), G6 = CLP (trained, tissue harvest at 24 h)
Fig. 13
Fig. 13
Integrative summary of the major observed effect in sepsis and exercise training on liver tissue and serum samples. A The panel shows the overview of the intersection of different potential key impacted Signaling pathways including inflammation, oxidative/nitrergic stress (redox balance), Hypoxia, and AGE/RAGE signaling in both Male and Female sepsis animals. B Pre-exercise training animals at post-operative hour 24. Pre-exercise training (3 weeks treadmill) significantly reduces the sepsis-induced molecular pathways destruction and increases sepsis survival. ↑, increased; ↓, decreased; ↕, no change/not significant change
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