Major elective abdominal surgery acutely impairs lower limb muscle pyruvate dehydrogenase complex activity and mitochondrial function

Ryan Atkins, Dumitru Constantin-Teodosiu, Krishna K Varadhan, Despina Constantin, Dileep N Lobo, Paul L Greenhaff, Ryan Atkins, Dumitru Constantin-Teodosiu, Krishna K Varadhan, Despina Constantin, Dileep N Lobo, Paul L Greenhaff

Abstract

Background & aims: This post hoc study aimed to determine whether major elective abdominal surgery had any acute impact on mitochondrial pyruvate dehydrogenase complex (PDC) activity and maximal mitochondrial ATP production rates (MAPR) in a large muscle group (vastus lateralis -VL) distant to the site of surgical trauma.

Methods: Fifteen patients undergoing major elective open abdominal surgery were studied. Muscle biopsies were obtained after the induction of anesthesia from the VL immediately before and after surgery for the determination of PDC and maximal MAPR (utilizing a variety of energy substrates).

Results: Muscle PDC activity was reduced by >50% at the end of surgery compared with pre-surgery (p < 0.05). Muscle MAPR were comprehensively suppressed by surgery for the substrate combinations: glutamate + succinate; glutamate + malate; palmitoylcarnitine + malate; and pyruvate + malate (all p < 0.05), and could not be explained by a lower mitochondrial yield.

Conclusions: PDC activity and mitochondrial ATP production capacity were acutely impaired in muscle distant to the site of surgical trauma. In keeping with the limited data available, we surmise these events resulted from the general anesthesia procedures employed and the surgery related trauma. These findings further the understanding of the acute dysregulation of mitochondrial function in muscle distant to the site of major surgical trauma in patients, and point to the combination of general anesthesia and trauma related inflammation as being drivers of muscle metabolic insult that warrants further investigation.

Clinical trial registration: Registered at (NCT01134809).

Keywords: Abdominal surgery; Metabolic response; Muscle inflammatory responses; Muscle mitochondrial activity; Pyruvate dehydrogenase complex.

Conflict of interest statement

Conflict of interest None of the authors has a direct conflict of interest to report. DN Lobo has received an unrestricted research grant for unrelated work from B. Braun in the last 3 years. He has also received speakers' honoraria from B. Braun, Fresenius Kabi, Shire and Baxter Healthcare for unrelated work in the last 3 years.

Copyright © 2020 The Author(s). Published by Elsevier Ltd.. All rights reserved.

Figures

Fig. 1
Fig. 1
Muscle pyruvate dehydrogenase complex (PDC) activity in vastus lateralis muscle pre and post major abdominal surgery. Values represent mean ± SEM and individual values. Difference between pre and post-surgery: ∗p 

Fig. 2

Maximal mitochondrial ATP production rates…

Fig. 2

Maximal mitochondrial ATP production rates in vastus lateralis muscle pre and post major…

Fig. 2
Maximal mitochondrial ATP production rates in vastus lateralis muscle pre and post major abdominal surgery. Maximal ATP production rates were determined utilizing the substrate combinations depicted on the X-axis. Values represent mean ± SEM and individual values. Differences between pre- and post-surgery: ∗p 
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References
    1. Thorell A., Nygren J., Ljungqvist O. Insulin resistance: a marker of surgical stress. Curr Opin Clin Nutr Metab Care. 1999;2:69–78. - PubMed
    1. Varadhan K.K., Constantin-Teodosiu D., Constantin D., Greenhaff P.L., Lobo D.N. Inflammation-mediated muscle metabolic dysregulation local and remote to the site of major abdominal surgery. Clin Nutr. 2018;37:2178–2185. - PMC - PubMed
    1. Hagve M., Gjessing P.F., Fuskevåg O.M., Larsen T.S., Irtun Ø. Skeletal muscle mitochondria exhibit decreased pyruvate oxidation capacity and increased ROS emission during surgery-induced acute insulin resistance. Am J Physiol Endocrinol Metab. 2015;308:E613–E620. - PubMed
    1. Gjessing P.F., Constantin-Teodosiu D., Hagve M., Lobo D.N., Revhaug A., Irtun O. Preoperative carbohydrate supplementation attenuates post-surgery insulin resistance via reduced inflammatory inhibition of the insulin-mediated restraint on muscle pyruvate dehydrogenase kinase 4 expression. Clin Nutr. 2015;34:1177–1183. - PubMed
    1. Alamdari N., Constantin-Teodosiu D., Murton A.J., Gardiner S.M., Bennett T., Layfield R. Temporal changes in the involvement of pyruvate dehydrogenase complex in muscle lactate accumulation during lipopolysaccharide infusion in rats. J Physiol. 2008;586:1767–1775. - PMC - PubMed
Show all 29 references
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Fig. 2
Fig. 2
Maximal mitochondrial ATP production rates in vastus lateralis muscle pre and post major abdominal surgery. Maximal ATP production rates were determined utilizing the substrate combinations depicted on the X-axis. Values represent mean ± SEM and individual values. Differences between pre- and post-surgery: ∗p 

References

    1. Thorell A., Nygren J., Ljungqvist O. Insulin resistance: a marker of surgical stress. Curr Opin Clin Nutr Metab Care. 1999;2:69–78.
    1. Varadhan K.K., Constantin-Teodosiu D., Constantin D., Greenhaff P.L., Lobo D.N. Inflammation-mediated muscle metabolic dysregulation local and remote to the site of major abdominal surgery. Clin Nutr. 2018;37:2178–2185.
    1. Hagve M., Gjessing P.F., Fuskevåg O.M., Larsen T.S., Irtun Ø. Skeletal muscle mitochondria exhibit decreased pyruvate oxidation capacity and increased ROS emission during surgery-induced acute insulin resistance. Am J Physiol Endocrinol Metab. 2015;308:E613–E620.
    1. Gjessing P.F., Constantin-Teodosiu D., Hagve M., Lobo D.N., Revhaug A., Irtun O. Preoperative carbohydrate supplementation attenuates post-surgery insulin resistance via reduced inflammatory inhibition of the insulin-mediated restraint on muscle pyruvate dehydrogenase kinase 4 expression. Clin Nutr. 2015;34:1177–1183.
    1. Alamdari N., Constantin-Teodosiu D., Murton A.J., Gardiner S.M., Bennett T., Layfield R. Temporal changes in the involvement of pyruvate dehydrogenase complex in muscle lactate accumulation during lipopolysaccharide infusion in rats. J Physiol. 2008;586:1767–1775.
    1. Constantin D., McCullough J., Mahajan R.P., Greenhaff P.L. Novel events in the molecular regulation of muscle mass in critically ill patients. J Physiol. 2011;589:3883–3895.
    1. Lopez-Armada M.J., Carames B., Martin M.A., Cillero-Pastor B., Lires-Dean M., Fuentes-Boquete I. Mitochondrial activity is modulated by TNFalpha and IL-1beta in normal human chondrocyte cells. Osteoarthritis Cartilage. 2006;14:1011–1022.
    1. Maneiro E., Lopez-Armada M.J., de Andres M.C., Carames B., Martin M.A., Bonilla A. Effect of nitric oxide on mitochondrial respiratory activity of human articular chondrocytes. Ann Rheum Dis. 2005;64:388–395.
    1. Stadler J., Bentz B.G., Harbrecht B.G., Di Silvio M., Curran R.D., Billiar T.R. Tumor necrosis factor alpha inhibits hepatocyte mitochondrial respiration. Ann Surg. 1992;216:539–546.
    1. Zell R., Geck P., Werdan K., Boekstegers P. TNF-alpha and IL-1 alpha inhibit both pyruvate dehydrogenase activity and mitochondrial function in cardiomyocytes: evidence for primary impairment of mitochondrial function. Mol Cell Biochem. 1997;177:61–67.
    1. Branca D., Varotto M.L., Vincenti E., Scutari G. General anesthetics: interferences with some mitochondrial energy-dependent mechanisms. Agressologie. 1989;30:79–83.
    1. Cohen P.J. Effect of anesthetics on mitochondrial function. Anesthesiology. 1973;39:153–164.
    1. Cohen P.J., Marshall B.E., Lecky J. Effects of halothane on mitochondrial oxygen uptake: site of action [abstract] Anesthesiology. 1969;30:337.
    1. Merin R.G., Verdouw P.D., de Jong J.W. Dose-dependent depression of cardiac function and metabolism by halothane in swine (Sus scrofa) Anesthesiology. 1977;46:417–423.
    1. Miller R.N., Hunter F.E., Jr. The effect of halothane on electron transport, oxidative phosphorylation, and swelling in rat liver mitochondria. Mol Pharmacol. 1970;6:67–77.
    1. Rigoulet M., Devin A., Averet N., Vandais B., Guerin B. Mechanisms of inhibition and uncoupling of respiration in isolated rat liver mitochondria by the general anesthetic 2,6-diisopropylphenol. Eur J Biochem. 1996;241:280–285.
    1. Krajcova A., Lovsletten N.G., Waldauf P., Fric V., Elkalaf M., Urban T. Effects of propofol on cellular bioenergetics in human skeletal muscle cells. Crit Care Med. 2018;46:e206–e212.
    1. Miro O., Barrientos A., Alonso J.R., Casademont J., Jarreta D., Urbano-Marquez A. Effects of general anaesthetic procedures on mitochondrial function of human skeletal muscle. Eur J Clin Pharmacol. 1999;55:35–41.
    1. Constantin-Teodosiu D., Cederblad G., Hultman E. A sensitive radioisotopic assay of pyruvate dehydrogenase complex in human muscle tissue. Anal Biochem. 1991;198:347–351.
    1. Wibom R., Hagenfeldt L., von Dobeln U. Measurement of ATP production and respiratory chain enzyme activities in mitochondria isolated from small muscle biopsy samples. Anal Biochem. 2002;311:139–151.
    1. Wibom R., Hultman E., Johansson M., Matherei K., Constantin-Teodosiu D., Schantz P.G. Adaptation of mitochondrial ATP production in human skeletal muscle to endurance training and detraining. J Appl Physiol (1985) 1992;73:2004–2010.
    1. Kremen J., Dolinkova M., Krajickova J., Blaha J., Anderlova K., Lacinova Z. Increased subcutaneous and epicardial adipose tissue production of proinflammatory cytokines in cardiac surgery patients: possible role in postoperative insulin resistance. J Clin Endocrinol Metab. 2006;91:4620–4627.
    1. Thorell A., Loftenius A., Andersson B., Ljungqvist O. Postoperative insulin resistance and circulating concentrations of stress hormones and cytokines. Clin Nutr. 1996;15:75–79.
    1. Witasp A., Nordfors L., Schalling M., Nygren J., Ljungqvist O., Thorell A. Increased expression of inflammatory pathway genes in skeletal muscle during surgery. Clin Nutr. 2009;28:291–298.
    1. Vary T.C. Regulation of skeletal muscle protein turnover during sepsis. Curr Opin Clin Nutr Metab Care. 1998;1:217–224.
    1. Navarra P., Tsagarakis S., Faria M.S., Rees L.H., Besser G.M., Grossman A.B. Interleukins-1 and -6 stimulate the release of corticotropin-releasing hormone-41 from rat hypothalamus in vitro via the eicosanoid cyclooxygenase pathway. Endocrinology. 1991;128:37–44.
    1. Constantin-Teodosiu D., Constantin D., Stephens F., Laithwaite D., Greenhaff P.L. The role of FOXO and PPAR transcription factors in diet-mediated inhibition of PDC activation and carbohydrate oxidation during exercise in humans and the role of pharmacological activation of PDC in overriding these changes. Diabetes. 2012;61:1017–1024.
    1. Randle P.J., Garland P.B., Hales C.N., Newsholme E.A. The glucose fatty-acid cycle. Its role in insulin sensitivity and the metabolic disturbances of diabetes mellitus. Lancet. 1963;1:785–789.
    1. Finsterer J., Segall L. Drugs interfering with mitochondrial disorders. Drug Chem Toxicol. 2010;33:138–151.

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