UBC Faculty Research and Publications

Metabolic changes in cardiomyocytes during sepsis Douglas, James J; Walley, Keith R Sep 20, 2013

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COMMENTARYMetabolic changes in card64not due to anaerobic metabolism, in accord with theobservations of Cunnion and colleagues [2]. Muscledata suggest that septic shock may have unique effects onDouglas and Walley Critical Care 2013, 17:186http://ccforum.com/content/17/5/186British Columbia, Division of Critical Care Medicine, Vancouver, BritishColumbia V6Z 1Y6, Canadaand impaired ventricular relaxation.pyruvate levels did not increase to the same extent dur-ing hemorrhagic shock, suggesting that increased lactatewas linked to anaerobic metabolism occurring in thisform of shock.This study demonstrated novel findings on the meta-bolic differences between two pathological shock states* Correspondence: Keith.Walley@hli.ubc.caCentre for Heart and Lung Innovation, St Paul's Hospital and University ofsubstrate utilization with accelerated glucose metabolism,despite comparable pyruvate and lactate levels [1]. Revers-ible cardiomyocyte hypocontractility also occurs, possiblyrelated to hibernation in order to maintain myocyte viabil-ity by limiting oxygen consumption, energy requirementsand ATP. Whether a direct metabolic link connectingmetabolic substrates and contractility exists remains to bedemonstrated. It is notable, however, that Chew and col-leagues [1] observed a significant drop in ejection fractionCardiomyocyte metabolism changes in response to dif-ferent types of shock. Chew and colleagues [1] in theprevious issue of Critical Care used microdialysis tomeasure metabolites within cardiac and skeletal muscleduring endotoxemia. They found that endotoxemicshock induces metabolic changes in cardiac and skeletalmuscle cells that do not occur during hemorrhagicshock. In particular, myocardial and skeletal muscleglucose concentrations were markedly decreased duringendotoxemic shock. While lactate increased in bothforms of shock, pyruvate levels also increased duringendotoxemia, suggesting that elevated lactate levels wereexpense of cardiac function. olism, including a reduction in the oxygen extraction ratioof the myocardium [2,3] and a shift in metabolic substratesepsisJames J Douglas and Keith R Walley*See related research by Chew et al., http://ccforum.com/content/17/4/R1AbstractDifferent types of shock induce distinct metabolicchanges. The myocardium at rest utilizes free fattyacids as its primary energy source, a mechanism thatchanges to aerobic glycolysis during sepsis and is incontrast to hemorrhagic shock. The immune systemalso uses this mechanism, changing its substrateutilization to activate innate and adaptive cells.Cardiomyocytes share a number of features similar toantigen-presenting cells and may use this mechanismto augment the immune response at the reversible© 2013 BioMed Central Ltd.iomyocytes duringand re-demonstrated the metabolic flexibility of themyocardium. The profoundly low local glucose concen-tration in myocardium and skeletal muscle duringendotoxemic shock with preservation of the lactate topyruvate ratios suggests lactate utilization and/or differ-ences in the Krebs cycle. Another interesting finding wasthe ability of skeletal muscle to preserve the lactate topyruvate ratio during endotoxemic but not hemorrhagicshock, reflecting again the different lactate fates andperhaps the different mitochondrial densities betweenmyocardium and skeletal muscle.Sepsis induces significant changes in myocardial metab-from using free fatty acids to increased utilization oflactate. To understand the differences in myocardial andskeletal muscle metabolism observed by Chew andcolleagues [1], we explore changes in substrate metabol-ism observed during a septic inflammatory response.Sepsis is unique amongst types of shock in that it is theresult of a complex interaction between the infectingmicroorganism and the host immune, inflammatory andcoagulation responses. The host innate immune response istriggered through interaction of pathogen molecules withinnate immune receptors with subsequent release of pro-and anti-inflammatory cytokines, stimulation of adaptiveimmunity, and activation of the coagulation system. Recent9. van der Windt GJ, Everts B, Chang CH, Curtis JD, Freitas TC, Amiel E, Pearcemetabolism and the T-cell response. Nat Rev Immunol 2005, 5:844–852.13. Chang CH, Curtis JD, Maggi LB Jr, Faubert B, Villarino AV, O'Sullivan D,Douglas and Walley Critical Care 2013, 17:186 Page 2 of 3http://ccforum.com/content/17/5/186Cardiomyocytes possess the ability to act as substrate'omnivores', changing their energy substrate in responseto demand, ischemia and inflammatory stimuli. Priorstudies have demonstrated the alteration in oxidativephosphorylation that occurs within mitochondria duringsepsis, despite adequate oxygen availability and the pres-ervation of ATP [4]. This also occurs during ischemia,likely from a different mechanism with intracellular ATPmaintained by increased aerobic glycolysis. Concur-rently, glucose transporters GLUT1 and GLUT4 increaseglucose uptake with glycogen deposition in the cells [5].The change in myocardial metabolism is not unique, butalso is a function of the immune system whereby immunecells must switch from a resting quiescent state to an activestate. Accelerated rates of glycolysis can occur throughlipopolysaccharide activation of macrophages and dendriticcells through Toll-like receptor 4 (TLR4) in M1 inflamma-tory macrophages and T-helper 17 lymphocytes [6,7]. Onthe other hand, cells that limit inflammation, such as regu-latory T cells, M2 anti-inflammatory macrophages and qui-escent memory T cells that carry the CD8 antigen, exhibitoxidative metabolism with more limited rates of glycolysis[8,9]. This process is very energy demanding and it hasbeen shown that activated T cells can increase glucose up-take 20- to 40-fold in preparation to divide [10]. Aminoacid and lipid metabolism is suppressed in order to permitcell expansion and hexokinase activity is increased, an en-zyme involved in both glycolysis and the catabolic pentosephosphate pathway [11]. Free fatty acids are also activatorsof NF-κB throughTLR4 signaling in adipocytes and skeletalmuscle, and may have a similar effect in the myocardium[12]. Therefore, aerobic glycolysis is required for immuneactivation of macrophages, dendritic cells and T-cell effec-tors, but has little effect on cell proliferation or survival [6].In activated T cells, this process may be regulated byGADPH binding to AU-rich elements in interferon-γmRNA, thereby controlling its cytokine translation [13].Cardiomyocytes share a number of features analogous tothe antigen-presenting cells, including expression of TLRs[14,15]. In response to TLR activation, cardiomyocytes ex-press many pro- and anti-inflammatory molecules, includ-ing cytokines (for example, tumor necrosis factor-α,interleukin-1β), chemokines, cell surface adhesions mole-cules, triggering of apoptotic pathways and increased ex-pression of calcium channel binding proteins. Intercellularadhesion molecule 1 binds the cardiomyocyte cytoskeleton,disrupting normal intracellular calcium release andresulting in decreased contractility [16]. Calcium channelbinding proteins S100A8 and S100A9 bind to the sarco-plasmic reticulum calcium channel SERCA2, further de-creasing contractility [17]. Lastly, extracellular heat shockprotein 70 acts through TLR2 to activate NF-κB and de-crease contractility [18]. Therefore, it is not surprising thatthe changes in myocardial metabolism observed during theHuang SC, van der Windt GJ, Blagih J, Qiu J, Weber JD, Pearce EJ, Jones RG,Pearce EL: Posttranscriptional control of T cell effector function byaerobic glycolysis. Cell 2013, 153:1239–1251.14. Brown MA, Jones WK: NF-kappaB action in sepsis: the innate immunesystem and the heart. Front Biosci 2004, 9:1201–1217.15. Boyd JH, Mathur S, Wang Y, Bateman RM, Walley KR: Toll-like receptorstimulation in cardiomyoctes decreases contractility and initiates an NF-kappaB dependent inflammatory response. Cardiovasc Res 2006,72:384–393.16. Davani EY, Dorscheid DR, Lee CH, van Breemen C, Walley KR: Novel12. Shi H, Kokoeva MV, Inouye K, Tzameli I, Yin H, Flier JS: TLR4 links innateimmunity and fatty acid-induced insulin resistance. J Clin Invest 2006,116:3015–3025.EJ, Pearce EL: Mitochondrial respiratory capacity is a critical regulator ofCD8+ T cell memory development. Immunity 2012, 36:68–78.10. Greiner EF, Guppy M, Brand K: Glucose is essential for proliferation andthe glycolytic enzyme induction that provokes a transition to glycolyticenergy production. J Biol Chem 1994, 269:31484–31490.11. Fox CJ, Hammerman PS, Thompson CB: Fuel feeds function: energyseptic inflammatory response may share features withchanges in metabolism observed in inflammatory cells. It isconceivable that changes in substrate metabolism observedin cardiomyocytes may be due to mechanisms shared withother inflammatory cells. Whether the myocardium de-creases contractility to reflect the relatively inefficientprocess of aerobic glycolysis remains to be solved.AbbreviationsNF: nuclear factor; TLR: Tol-like receptor.Competing interestsThe authors declare that they have no competing interests.Published: 20 September 2013References1. Chew MS, Shekare K, Brand BA, Norin C, Barnett AG: Depletion ofmyocardial glucose is observed during endotoxaemic but nothaemorrhagic shock in a porcine model. Crit Care 2013, 17:R164.2. Cunnion RE, Schaer GL, Parker MM, Natanson C, Parrillo JE: The coronarycirculation in human septic shock. Circulation 1986, 73:637–644.3. Dhainaut JF, Huyghebaert MF, Monsallier JF, Lefevre G, Dall'Ava-Santucci J,Brunet F, Villemant D, Carli A, Raichvarg D: Coronary hemodynamics andmyocardial metabolism of lactate, free fatty acids, glucose, and ketonesin patients with septic shock. Circulation 1987, 75:533–541.4. Fink MP: Bench-to-bedside review: Cytopathic hypoxia. Crit Care 2002,6:491–499.5. Tian R, Abel ED: Responses of GLUT4-deficient hearts to ischemiaunderscore the importance of glycolysis. Circulation 2001, 103:2961–2966.6. Krawczyk CM, Holowka T, Sun J, Blagih J, Amiel E, DeBerardinis RJ, Cross JR,Jung E, Thompson CB, Jones RG, Pearce EJ: Toll-like receptor-inducedchanges in glycolytic metabolism regulate dendritic cell activation. Blood2010, 115:4742–4749.7. Rodriguez-Prados JC, Traves PG, Cuenca J, Rico D, Aragones J, Martin-Sanz P,Cascante M, Bosca L: Substrate fate in activated macrophages: a comparisonbetween innate, classic, and alternative activation. J Immunol 2010,185:605–614.8. Shi LZ, Wang R, Huang G, Vogel P, Neale G, Green DR, Chi H: HIF1alpha-dependent glycolytic pathway orchestrates a metabolic checkpoint forthe differentiation of TH17 and Treg cells. J Exp Med 2011, 208:1367–1376.regulatory mechanism of cardiomyocyte contractility involving ICAM-1 and the cytoskeleton. Am J Physiol Heart Circ Physiol 2004, 287:H1013–H1022.17. Boyd JH, Kan B, Roberts H, Wang Y, Walley KR: S100A8 and S100A9mediate endotoxin-induced cardiomyocyte dysfunction via the receptorfor advanced glycation end products. Circ Res 2008, 102:1239–1246.18. Mathur S, Walley KR, Wang Y, Indrambarya T, Boyd JH: Extracellular heatshock protein 70 induces cardiomyocyte inflammation and contractiledysfunction via TLR2. Circ J 2011, 75:2445–2452.doi:10.1186/1364-8535-17-186Cite this article as: Douglas and Walley: Metabolic changes incardiomyocytes during sepsis. Critical Care 2013 17:186Douglas and Walley Critical Care 2013, 17:186 Page 3 of 3http://ccforum.com/content/17/5/186


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