Impaired mitochondrial capacity may be implicated in the pathology of chronic metabolic diseases. To elucidate the effect of ethyl pyruvate supplementation on skeletal muscles metabolism we examined changes in activities of mitochondrial and antioxidant enzymes, as well as sulfhydryl groups oxidation (an indirect marker of oxidative stress) during the development of obesity. After 6 weeks feeding of control or high fat diet, Wistar rats were divided into four groups: control diet, control diet and ethyl pyruvate, high fat diet, and high fat diet and ethyl pyruvate. Ethyl pyruvate was administered as 0.3% solution in drinking water, for the following 6 weeks. High fat diet feeding induced the increase of activities 3-hydroxyacylCoA dehydrogenase, citrate synthase, and fumarase. Moreover, higher catalase and superoxide dismutase activities, as well as sulfhydryl groups oxidation, were noted. Ethyl pyruvate supplementation did not affect the mitochondrial enzymes’ activities, but induced superoxide dismutase activity and sulfhydryl groups oxidation. All of the changes were observed in soleus muscle, but not in extensor digitorum longus muscle. Additionally, positive correlations between fasting blood insulin concentration and activities of catalase ( p = 0.04), and superoxide dismutase ( p = 0.01) in soleus muscle were noticed. Prolonged ethyl pyruvate consumption elevated insulin concentration, which may cause modifications in oxidative type skeletal muscles.
References
[1]
Johannsen, D.L.; Ravussin, E. The role of mitochondria in health and disease. Curr. Opin. Pharmacol. 2009, 9, 780–786, doi:10.1016/j.coph.2009.09.002.
[2]
Parise, G.; de Lisio, M. Mitochondrial theory of aging in human age-related sarcopenia. Interdiscip. Top. Gerontol. 2010, 37, 142–156.
[3]
Iossa, S.; Lionetti, L.; Mollica, M.P.; Crescenzo, R.; Botta, M.; Barletta, A.; Liverini, G. Effect of high-fat feeding on metabolic efficiency and mitochondrial oxidative capacity in adult rats. Br. J. Nutr. 2003, 90, 953–960, doi:10.1079/BJN2003000968.
[4]
Chanseaume, E.; Malpuech-Brugere, C.; Patrac, V.; Bielicki, G.; Rousset, P.; Couturier, K.; Salles, J.; Renou, J.P.; Boirie, Y.; Morio, B. Diets high in sugar, fat, and energy induce muscle type-specific adaptations in mitochondrial functions in rats. J. Nutr. 2006, 136, 2194–2200.
[5]
Lionetti, L.; Mollica, M.P.; Crescenzo, R.; D’Andrea, E.; Ferraro, M.; Bianco, F.; Liverini, G.; Iossa, S. Skeletal muscle subsarcolemmal mitochondrial dysfunction in high-fat fed rats exhibiting impaired glucose homeostasis. Int. J. Obes. (Lond.) 2007, 31, 1596–1604, doi:10.1038/sj.ijo.0803636.
[6]
Chanseaume, E.; Tardy, A.L.; Salles, J.; Giraudet, C.; Rousset, P.; Tissandier, A.; Boirie, Y.; Morio, B. Chronological approach of diet-induced alterations in muscle mitochondrial functions in rats. Obesity (Silver Spring) 2007, 15, 50–59.
[7]
Takada, S.; Kinugawa, S.; Hirabayashi, K.; Suga, T.; Yokota, T.; Takahashi, M.; Fukushima, A.; Homma, T.; Ono, T.; Sobirin, M.A.; et al. Angiotensin II receptor blocker improves the lowered exercise capacity and impaired mitochondrial function of the skeletal muscle in type 2 diabetic mice. J. Appl. Physiol. 2013, 114, 844–857, doi:10.1152/japplphysiol.00053.2012.
[8]
Yokota, T.; Kinugawa, S.; Hirabayashi, K.; Matsushima, S.; Inoue, N.; Ohta, Y.; Hamaguchi, S.; Sobirin, M.A.; Ono, T.; Suga, T.; et al. Oxidative stress in skeletal muscle impairs mitochondrial respiration and limits exercise capacity in type 2 diabetic mice. Am. J. Physiol. Heart Circ. Physiol. 2009, 297, H1069–H1077, doi:10.1152/ajpheart.00267.2009.
[9]
Yuzefovych, L.V.; Musiyenko, S.I.; Wilson, G.L.; Rachek, L.I. Mitochondrial DNA damage and dysfunction, and oxidative stress are associated with endoplasmic reticulum stress, protein degradation and apoptosis in high fat diet-induced insulin resistance mice. PLoS One 2013, 8, e54059, doi:10.1371/journal.pone.0054059.
[10]
St Pierre, J.; Buckingham, J.A.; Roebuck, S.J.; Brand, M.D. Topology of superoxide production fromdifferent sites in the mitochondrial electron transport chain. J. Biol. Chem. 2002, 277, 44784–44790.
[11]
Barazzoni, R.; Zanetti, M.; Cappellari, G.G.; Semolic, A.; Boschelle, M.; Codarin, E.; Pirulli, A.; Cattin, L.; Guarnieri, G. Fatty acids acutely enhance insulin-induced oxidative stress and cause insulin resistance by increasing mitochondrial reactive oxygen species (ROS) generation and nuclear factor-κB inhibitor (IκB)-nuclear factor-κB (NFκB) activation in rat muscle, in the absence of mitochondrial dysfunction. Diabetologia 2012, 55, 773–782, doi:10.1007/s00125-011-2396-x.
[12]
Wells, G.D.; Noseworthy, M.D.; Hamilton, J.; Tarnopolski, M.; Tein, I. Skeletal muscle metabolic dysfunction in obesity and metabolic syndrome. Can. J. Neurol. Sci. 2008, 35, 31–40.
[13]
Rogge, M.M. The role of impaired mitochondrial lipid oxidation in obesity. Biol. Res. Nurs. 2009, 10, 356–373, doi:10.1177/1099800408329408.
[14]
Chanseaume, E.; Morio, B. Potential mechanisms of muscle mitochondrial dysfunction in aging and obesity and cellular consequences. Int. J. Mol. Sci. 2009, 10, 306–324, doi:10.3390/ijms10010306.
[15]
Zorzano, A.; Hernandez-Alvarez, M.I.; Palacin, M.; Mingrone, G. Alterations in the mitochondrial regulatory pathways constituted by the nuclear co-factors PGC-1α or PGC-1β and mitofusin 2 in skeletal muscle in type 2 diabetes. Biochim. Biophys. Acta 2010, 1797, 1028–1033, doi:10.1016/j.bbabio.2010.02.017.
[16]
Wilson, L.; Yang, Q.; Szustakowski, J.D.; Gullicksen, P.S.; Halse, R. Pyruvate induces mitochondrial biogenesis by a PGC-1 α-independent mechanism. Am. J. Physiol. Cell Physiol. 2007, 292, C1599–C1605, doi:10.1152/ajprenal.00473.2006.
[17]
Owen, L.; Sunram-Lea, S.I. Metabolic agents that enhance ATP can improve cognitive functioning: A review of the evidence for glucose, oxygen, pyruvate, creatine, and l-carnitne. Nutrients 2011, 3, 735–755.
[18]
Ivy, J.L.; Cortez, M.Y.; Chandler, R.M.; Byrne, H.K.; Miller, R.H. Effects of pyruvate on the metabolism and insulin resistance of obese Zucker rats. Am. J. Clin. Nutr. 1994, 59, 331–337.
[19]
Das, U.N. Pyruvate is an endogenous anti-inflammatory and anti-oxidant molecule. Med. Sci. Monit. 2006, 12, RA79–RA84.
[20]
Bunton, C.A. Oxidation of a-diketones and a-keto-acids by hydrogen peroxide. Nature 1949, 163, 444.
[21]
Dobsak, P.; Courderot-Masuyer, C.; Zeller, M.; Vergely, C.; Laubriet, A.; Assem, M.; Eicher, J.C.; Teyssier, J.R.; Wolf, J.E.; Rochette, L. Antioxidative properties of pyruvate and protection of the ischemic rat heart during cardioplegia. J. Cardiovasc. Pharmacol. 1999, 34, 651–659, doi:10.1097/00005344-199911000-00005.
[22]
Cruz, R.J., Jr.; Harada, T.; Sasatomi, E.; Fink, M.P. Effects of ethyl pyruvate and other alpha-keto carboxylic acid derivatives in a rat model of multivisceral ischemia and reperfusion. J. Surg. Res. 2011, 165, 151–157, doi:10.1016/j.jss.2009.07.008.
[23]
Olek, R.A.; Ziolkowski, W.; Kaczor, J.J.; Wierzba, T.H.; Antosiewicz, J. Higher hypochlorous acid scavenging activity of ethyl pyruvate compared to its sodium salt. Biosci. Biotechnol. Biochem. 2011, 75, 500–504, doi:10.1271/bbb.100728.
[24]
Johansson, A.S.; Johansson-Haque, K.; Okret, S.; Palmblad, J. Ethyl pyruvate modulates acute inflammatory reactions in human endothelial cells in relation to the NF-kappaB pathway. Br. J. Pharmacol. 2008, 154, 1318–1326, doi:10.1038/bjp.2008.201.
[25]
Kim, J.B.; Yu, Y.M.; Kim, S.W.; Lee, J.K. Anti-inflammatory mechanism is involved in ethyl pyruvate-mediated efficacious neuroprotection in the postischemic brain. Brain Res. 2005, 1060, 188–192.
[26]
Zeng, J.; Liu, J.; Yang, G.Y.; Kelly, M.J.; James, T.L.; Litt, L. Exogenous ethyl pyruvate versus pyruvate during metabolic recovery after oxidative stress in neonatal rat cerebrocortical slices. Anesthesiology 2007, 107, 630–640.
[27]
Fedeli, D.; Falcioni, G.; Olek, R.A.; Massi, M.; Cifani, C.; Polidori, C.; Gabbianelli, R. Protective effect of ethyl pyruvate on msP rat leukocytes damaged by alcohol intake. J. Appl. Toxicol. 2007, 27, 561–570, doi:10.1002/jat.1236.
[28]
Olek, R.A.; Ziolkowski, W.; Flis, D.J.; Fedeli, D.; Fiorini, D.; Wierzba, T.H.; Gabbianelli, R. The effect of ethyl pyruvate supplementation on rat fatty liver induced by high fat diet. J. Nutr. Sci. Vitaminol. (Tokyo) 2013. in press.
Lowry, O.H.; Rosebrough, N.J.; Farr, A.L.; Randall, R.J. Protein measurement with the Folin phenol reagent. J. Biol. Chem. 1951, 193, 265–275.
[31]
Hancock, C.R.; Han, D.H.; Chen, M.; Terada, S.; Yasuda, T.; Wright, D.C.; Holloszy, J.O. High-fat diets cause insulin resistance despite an increase in muscle mitochondria. Proc. Natl. Acad. Sci. USA 2008, 105, 7815–7820.
[32]
Van den Broek, N.M.; Ciapaite, J.; de Feyter, H.M.; Houten, S.M.; Wanders, R.J.; Jeneson, J.A.; Nicolay, K.; Prompers, J.J. Increased mitochondrial content rescues in vivo muscle oxidative capacity in long-term high-fat-diet-fed rats. FASEB J. 2010, 24, 1354–1364, doi:10.1096/fj.09-143842.
[33]
Turner, N.; Bruce, C.R.; Beale, S.M.; Hoehn, K.L.; So, T.; Rolph, M.S.; Cooney, G.J. Excess lipid availability increases mitochondrial fatty acid oxidative capacity in muscle: Evidence against a role for reduced fatty acid oxidation in lipid-induced insulin resistance in rodents. Diabetes 2007, 56, 2085–2092, doi:10.2337/db07-0093.
[34]
Wright, L.E.; Brandon, A.E.; Hoy, A.J.; Forsberg, G.B.; Lelliott, C.J.; Reznick, J.; Lofgren, L.; Oscarsson, J.; Stromstedt, M.; Cooney, G.J.; et al. Amelioration of lipid-induced insulin resistance in rat skeletal muscle by overexpression of Pgc-1β involves reductions in long-chain acyl-CoA levels and oxidative stress. Diabetologia 2011, 54, 1417–1426, doi:10.1007/s00125-011-2068-x.
[35]
Iossa, S.; Mollica, M.P.; Lionetti, L.; Crescenzo, R.; Botta, M.; Liverini, G. Skeletal muscle oxidative capacity in rats fed high-fat diet. Int. J. Obes. Relat. Metab. Disord. 2002, 26, 65–72, doi:10.1038/sj.ijo.0801844.
[36]
Zou, B.; Suwa, M.; Nakano, H.; Higaki, Y.; Ito, T.; Katsuta, S.; Kumagai, S. Adaptation of skeletal muscle characteristics to a high-fat diet in rats with different intra-abdominal-obesity susceptibilities. J. Nutr. Sci. Vitaminol. (Tokyo) 2003, 49, 241–246, doi:10.3177/jnsv.49.241.
[37]
Ritchie, I.R.; Dyck, D.J. Rapid loss of adiponectin-stimulated fatty acid oxidation in skeletal muscle of rats fed a high fat diet is not due to altered muscle redox state. PLoS One 2012, 7, e52193, doi:10.1371/journal.pone.0052193.
[38]
Campbell, S.E.; Tandon, N.N.; Woldegiorgis, G.; Luiken, J.J.; Glatz, J.F.; Bonen, A. A novel function for fatty acid translocase (FAT)/CD36: Involvement in long chain fatty acid transfer into the mitochondria. J. Biol. Chem. 2004, 279, 36235–36241.
[39]
Bonen, A.; Holloway, G.P.; Tandon, N.N.; Han, X.X.; McFarlan, J.; Glatz, J.F.; Luiken, J.J. Cardiac and skeletal muscle fatty acid transport and transporters and triacylglycerol and fatty acid oxidation in lean and Zucker diabetic fatty rats. Am. J. Physiol. 2009, 297, R1202–R1212.
[40]
Seifert, E.L.; Estey, C.; Xuan, J.Y.; Harper, M.E. Electron transport chain-dependent and -independent mechanisms of mitochondrial H2O2 emission during long-chain fatty acid oxidation. J. Biol. Chem. 2010, 285, 5748–5758.
[41]
Montgomery, C.M.; Webb, J.L. Metabolic studies on heart mitochondria. II. The inhibitory action of parapyruvate on the tricarboxylic acid cycle. J. Biol. Chem. 1956, 221, 359–368.
[42]
Kao, K.K.; Fink, M.P. The biochemical basis for the anti-inflammatory and cytoprotective actions of ethyl pyruvate and related compounds. Biochem. Pharmacol. 2010, 80, 151–159, doi:10.1016/j.bcp.2010.03.007.
[43]
Kim, S.Y.; Choi, J.S.; Park, C.; Jeong, J.W. Ethyl pyruvate stabilizes hypoxia-inducible factor 1 alpha via stimulation of the TCA cycle. Cancer Lett. 2010, 295, 236–241, doi:10.1016/j.canlet.2010.03.006.
[44]
Chen, J.; Ma, H.T.; Wang, M.; Kong, Y.L.; Zou, S.X. Creatine pyruvate enhances lipolysis and protein synthesis in broiler chicken. J. Integr. Agric. 2011, 10, 1977–1985.
