Prehabilitation Ameliorates Gut Ischemia Reperfusion Injury in Mice

Published:October 15, 2022DOI:



      We previously demonstrated that prehabilitation by running on a treadmill leads to improved survival after gut ischemia reperfusion (I/R) in mice. The purpose of this research was to examine whether prehabilitation attenuates inflammatory responses after gut I/R in mice.

      Materials and methods

      Male C57BL/6J mice (n = 92) were assigned to the sedentary (n = 46) or the exercise (n = 46) group. The exercise group ran on a treadmill for 4 wk, while the sedentary mice did not exercise. After the 4-week pretreatment, all mice underwent gut I/R and the blood, urine, small intestine, lung, liver, and gastrocnemius were harvested prior to ischemia or at 0, 3, 6, or 24 h after reperfusion. Histologically demonstrated organ damage, cytokine levels in the blood, gut and gastrocnemius, myeloperoxidase activity in the gut, 8-hydroxy-2′-deoxyguanosine levels in urine and the gut, and adenosine triphosphate (ATP) and ATP + ADP + adenosine monophosphate levels in the gut and gastrocnemius were evaluated.


      The treadmill exercise reduced gut and lung injuries at 3 h and liver injury at 6 h after reperfusion. Running on the treadmill also decreased proinflammatory cytokine levels in the blood at 6 h, gut at 3 h and gastrocnemius at 6 h after reperfusion, myeloperoxidase activity in the gut prior to ischemia, and 6 h after reperfusion and the urinary 8-hydroxy-2′-deoxyguanosine level at 24 h after reperfusion, while ATP levels in exercised mice prior to ischemia and 3 h after reperfusion were increased in the intestine as compared to the levels in sedentary mice.


      Prehabilitation with treadmill exercise reduces inflammatory responses after gut I/R and may exert protective actions against gut I/R.


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        • Pędziwiatr M.
        • Mavrikis J.
        • Nowakowski M.
        • et al.
        Current status of enhanced recovery after surgery (ERAS) protocol in gastrointestinal surgery.
        Med Oncol. 2018; 35: 95
        • Adamina M.
        • Kehlet H.
        • Delaney C.P.
        • et al.
        Enhanced recovery pathways optimize health outcomes and resource utilization: a meta-analysis of randomized controlled trials in colorectal surgery.
        Surgery. 2011; 149: 830-840
        • Melchior J.C.
        • Préaud E.
        • Nitenberg G.
        • et al.
        Clinical and economic impact of malnutrition per se on the postoperative course of colorectal cancer patients.
        Clin Nutr. 2012; 31: 896-902
        • Higashizono K.
        • Fukatsu K.
        • Seto Y.
        • et al.
        Appropriate treadmill exercise improves survival after gut ischemia reperfusion in mice.
        Clin Nutr Exp. 2019; 25: 36-41
        • Higashizono K.
        • Fukatsu K.
        • Seto Y.
        • et al.
        Influences of short-term fasting and carbohydrate supplementation on gut immunity and mucosal morphology in mice.
        JPEN J Parenter Enteral Nutr. 2019; 43: 516-524
        • Gillis C.
        • Buhler K.
        • Fenton T.R.
        • et al.
        Effects of nutritional prehabilitation, with and without exercise, on outcomes of patients who undergo colorectal surgery: a systematic review and meta-analysis.
        Gastroenterology. 2018; 155: 391-410.e4
        • Weimann A.
        • Braga M.
        • Singer P.
        • et al.
        ESPEN guideline: clinical nutrition in surgery.
        Clin Nutr. 2017; 36: 623-650
        • Fukuda Y.
        • Yamamoto K.
        • Tsujinaka T.
        • et al.
        Sarcopenia is associated with severe postoperative complications in elderly gastric cancer patients undergoing gastrectomy.
        Gastric Cancer. 2016; 19: 986-993
        • Moore F.A.
        The role of the gastrointestinal tract in postinjury multiple organ failure.
        Am J Surg. 1999; 178: 449-453
        • Collange O.
        • Charles A.L.
        • Geny B.
        • et al.
        Compartmentalization of inflammatory response following gut ischemia reperfusion.
        Eur J Vasc Endovasc Surg. 2015; 49: 60-65
        • Kong S.E.
        • Blennerhassett L.R.
        • Hall J.C.
        • et al.
        Ischemia-reperfusion injury to the intestine.
        Aust N Z J Surg. 1998; 68: 554-561
        • Moore E.E.
        • Moore F.A.
        • Banerjee A.
        • et al.
        The postischemic gut serves as a priming bed for circulating neutrophils that provoke multiple organ failure.
        J Trauma. 1994; 37: 881-887
        • Otaka N.
        • Shibata R.
        • Ouchi N.
        • et al.
        Myonectin is an exercise-induced myokine that protects the heart from ischemia-reperfusion injury.
        Circ Res. 2018; 123: 1326-1338
        • Petersen A.M.W.
        • Pedersen B.K.
        The anti-inflammatory effect of exercise.
        J Appl Physiol (1985). 2005; 98: 1154-1162
        • Fallon K.E.
        • Fallon S.K.
        • Boston T.
        The acute phase response and exercise: court and field sports.
        Br J Sports Med. 2001; 35: 170-173
        • Mattusch F.
        • Dufaux B.
        • Rost R.
        • et al.
        Reduction of the plasma concentration of C-reactive protein following nine months of endurance training.
        Int J Sports Med. 2000; 21: 21-24
        • Drenth J.P.
        • Van Uum S.H.
        • Van der Meer J.W.
        • et al.
        Endurance run increases circulating IL-6 and IL-1ra but downregulates ex vivo TNF-alpha and IL-1 beta production.
        J Appl Physiol (1985). 1995; 79: 1497-1503
        • Buvinic S.
        • Almarza G.
        • Jaimovich E.
        • et al.
        ATP released by electrical stimuli elicits calcium transients and gene expression in skeletal muscle.
        J Biol Chem. 2009; 284: 34490-34505
        • Streensberg A.
        • van Hall G.
        • Pedersen B.K.
        • et al.
        Production of interleukin-6 in contracting human skeletal muscles can account for the exercise-induced increase in plasma interleukin-6.
        J Physiol. 2000; 529: 237-242
        • Mesole S.B.
        • Alfred O.O.
        • Ndhlovu D.
        • et al.
        Apoptotic inducement of neuronal cells by aluminum chloride and the neuroprotective effect of eugenol in wister rats.
        Oxid Med Cell Longev. 2020; 2020: 8425643
        • Pen Y.
        • Yang Q.
        • Ye J.
        • et al.
        IL-6 protects cardiomyocytes from oxidative stress at the early stage of LPS-induced sepsis.
        Biochem Biophys Res Commun. 2022; 603: 144-152
        • Chiu C.J.
        • McArdle A.H.
        • Gurd F.N.
        • et al.
        Intestinal mucosal lesion in low-flow states. I. A morphological, hemodynamic, and metabolic reappraisal.
        Arch Surg. 1970; 101: 478-483
        • Zhu Q.
        • He G.
        • Chen W.
        • et al.
        Protective effects of fenofibrate against acute lung injury induced by intestinal ischemia/reperfusion in mice.
        Sci Rep. 2016; 6: 22044
        • Suzuki S.
        • Toledo-Pereyra L.H.
        • Cejalvo D.
        • et al.
        Neutrophil infiltration as an important factor in liver ischemia and reperfusion injury. Modulating effects of FK506 and cyclosporine.
        Transplantation. 1993; 55: 1265-1272
        • Neto CAdSF.
        • Koike M.K.
        • Saad K.R.
        • et al.
        Effects of ischemic preconditioning and cilostazol on muscle ischemia-reperfusion injury in rats.
        Acta Cir Bras. 2014; 29: 17-21
        • Arroyo M.G.
        • Ferreira A.M.
        • de Almeida M.T.G.
        • et al.
        Effectiveness of ATP bioluminescence assay for presumptive identification of microorganisms in hospital water sources.
        BMC Infect Dis. 2017; 17: 458
        • Bakke M.
        • Suzuki S.
        Development of a novel hygiene monitoring system based on the detection of total adenylate (ATP+ADP+AMP).
        J Food Prot. 2018; 81: 729-737
        • Bay M.L.
        • Pedersen B.K.
        Muscle-organ crosstalk: focus on immunometabolism.
        Front Physiol. 2020; 11: 567881
        • Wu M.Y.
        • Yiang G.T.
        • Liao W.T.
        Current mechanistic concepts in ischemia and reperfusion injury.
        Cell Physiol Biochem. 2018; 46: 1650-1667
        • Ornellas F.M.
        • Ornellas D.S.
        • Morales M.M.
        • et al.
        Bone marrow-derived mononuclear cell therapy accelerates renal ischemia-reperfusion injury recovery by modulating inflammatory, antioxidant and apoptotic related molecules.
        Cell Physiol Biochem. 2017; 41: 1736-1752
        • Tao L.
        • Bei Y.
        • Li X.
        • et al.
        Exercise training protects against acute myocardial infraction via improving myocardial energy metabolism and mitochondrial biogenesis.
        Cell Physiol Biochem. 2015; 37: 162-175
        • Biffl W.L.
        • Moore E.E.
        • Franciose R.J.
        • et al.
        Interleukin-6 potentiates neutrophil priming with platelet-activating factor.
        Arch Surg. 1994; 129: 1131-1136
        • Matsukawa A.
        • Hogaboam C.M.
        • Kunkel S.L.
        • et al.
        Endogenous monocyte chemoattractant protein-1 (MCP-1) protects mice in a model of acute septic peritonitis: cross-talk between MCP-1 and leukotriene B4.
        J Immunol. 1999; 163: 6148-6154
        • Mallick I.H.
        • Yang W.
        • Seifalian A.M.
        • et al.
        Ischemia-reperfusion injury of the intestine and protective strategies against injury.
        Dig Dis Sci. 2004; 49: 1359-1377
        • Aruoma O.I.
        • Cuppett S.L.
        Antioxidant Methodology: In-Vivo and In-Vitro Concepts.
        American Oil Chemists, Illinois, USA1997
        • Nakajima H.
        • Yokoyama Y.
        • Nagino M.
        • et al.
        Clinical Benefit of preoperative exercise and nutritional therapy for patients undergoing hepato-pancreato-biliary surgeries for malignancy.
        Ann Surg Oncol. 2019; 26: 264-272