Issue
L-Carnitine supplementation increases expression of PPAR-γ and glucose transporters in skeletal muscle of chronically and acutely exercised rats
Corresponding Author(s) : Kazim Sahin
Cellular and Molecular Biology,
Vol. 64 No. 1: Issue 1
Abstract
In this study, the effects of L-Carnitine supplementation on the lipid peroxidation and expression of PPAR-γ and glucose transporters in the liver and muscles of chronically and acutely exercised rats were investigated. A total of 42 male Wistar Albino rats (8-week-old) were divided into six groups as follows: Control, L-Carnitine, Chronic Exercise (CE), Chronic Exercise + L-Carnitine, Acute Exercise (AE) and L-Carnitine + Acute Exercise. Chronic exercise consists of 30 m/min, 30 min/day, and 5 days/week for 6 weeks. Rats in the acute exercise groups were run on the treadmill at 30 m/min until exhaustion. L-Carnitine was given at the level of 300 mg per kilogram of diet for 6 weeks. There was no significant difference in the levels of serum ALT, AST, urea, creatinine and glucose levels between the exercise and L-Carnitine groups (P > 0.05). Cholesterol and triglyceride levels decreased by L- carnitine supplementation and chronic exercise in control groups but increased in the AE groups compared to the control group without reinforcement (P < 0.05). Serum, muscle, heart, and liver malondialdehyde (MDA) concentrations were lower in CE and higher in the AE groups (P < 0.001). However, L-Carnitine supplementation reduced MDA levels (P < 0.05). Liver and muscle PPAR-γ, liver GLUT-2 and muscle GLUT-4 mRNA expressions were lower in AE group than in all other groups (P < 0.001). Both chronic exercise and supplemental L-Carnitine increased liver and muscle PPAR-γ, GLUT-2 and GLUT-4 mRNA expression (P <0.05). As a result, although acute exercise increased oxidative stress, chronic exercise reduced oxidative stress by lowering lipid peroxidation level. L-Carnitine supplementation decreased oxidative stress and improved glucose and lipid metabolism by regulation of PPAR-γ, GLUT-2 and GLUT-4 mRNA expression in rats.
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- References
- Lambertucci RH, Levada-Pires AC, Rossoni LV, Curi R, Pithon-Curi TC. Effects of aerobic exercise training on antioxidant enzyme activities and mRNA levels in soleus muscle from young and aged rats. Mech Ageing Dev 2007;128:267-75.
- Powers SK, Jackson MJ. Exercise-induced oxidative stress: cellular mechanisms and impact on muscle force production. Physiol Rev 2008; 88:1243-76.
- Sjödin B, HellstenWesting Y, Apple FS. Biochemical mechanisms for oxygen free radical formation during exercise. Sports Med 1990; 10:236-54.
- Hartmann A, Niess A. In: Oxidative DNA damage in exercise. Sen C; Packer L; Hanninen O, (eds.), Handbook of oxidants and antioxidants in exercise. Elsevier, Amsterdam, 2000, pp. 195-217
- Halliwell B, Gutteridge JMC. Free radicals in biology and medicine., Oxford Univ, New York, 1999.
- Young IM, Thomson K. Spinning-induced rhabdomyolysis: a case report. Eur J Emerg Med 2004; 11:358-9.
- Crentsil V. Mechanistic contribution of carnitine deficiency to geriatric frailty. Aging Res Rev 2010; 9:265-268.
- Li J, Zhang Y, Luan H, Chen X, Han Y, Wang C. L-Carnitine protects human hepatocytes from oxidative stress-induced toxicity through Akt-mediated activation of Nrf2 signaling pathway. Can J Physiol Pharmacol 2016; 94:517-25.
- Ronsen O. Supplement use and nutritional habits in norwegion elite athletes. Scand J Med Sci Sports 1999; 9:28-35.
- Tashiro K, Kawabata K, Sakurai H, Kurachi S, Sakurai F, Yamanishi K et al. Efficient adenovirus vector-mediated PPAR gamma gene transfer into mouse embryoid bodies promotes adipocyte differentiation. J Gene Med 2008; 10:498-507.
- Nicholson AC. Expression of CD36 in macrophages and atherosclerosis: the role of lipid regulation of PPARgamma signaling. Trends Cardiovasc Med 2004;14: 8-12.
- Rosenson RS. Effects of peroxisome proliferator-activated receptors on lipoprotein metabolism and glucose control in type 2 diyabetes mellitus. Am J Cardiol 2007; 99:96-104.
- Varga T, Nagy L. Nuclear receptors, transcription factors linking lipid metabolism and immunity: the case of peroxisome proliferator-activated receptor gamma. Eur J Clin Invest 2008; 38:695-707.
- Cock TA, Houten SM, Auwerx J. Peroxisome proliferator- activated receptor γ :too much of a good thing cause harm. EMBO Rep 2004; 5:142-147.
- Yang J, Holman GD. Long-term metformin treatment stimulates cardiomyocyte glucose transport through an AMP-activated protein kinase dependent reduction in GLUT4 endocytosis. Endocrinology 2006; 147:2728-36.
- Goodyear LJ, Kahn BB. Exercise glucose transport, and insulin sensitivity. Annu Rev Med 1998; 49:235-61.
- Mizock B. Alterations in fuel metabolism in critical illness: hyperglycaemia. Best Pract Res Clin Endocrinol Metab 2001; 15:533-551.
- Powers SK, Jackson MJ. Exercise-induced oxidative stress: cellular mechanisms and impact on muscle force production. Physiol Rev 2008; 88:1243-76.
- Gülçin ć°. Antioxidant and antiradical activities of L-Carnitine. Life sci 2006; 78:803-811.
- Feng Y, Guo C, Weı J, Yang J, Ge Y, Gao L. Necessity of carnitine supplementation in semistarved rats fed a high-fat diet. Nutrition 2001; 7:628-631.
- Rani PJ, Panneerselvam C. Protective efficacy of L-Carnitine on acetylcholinesterase activity in aged rat brain. J Gerontol A Biol Sci Med Sci 2001; 56:140-141.
- Karatepe M. Simultaneous determination of ascorbic acid and free malondialdehyde in human serum by HPLC-UV. Lc Gc North America 2004; 22:362-365.
- Balh JJ, Bressler R. The pharmacology of carnitine. Ann Rev Pharmacol Toxicol 1987; 27:257-77.
- Zelnik N, Fridkis S, Gruener N. Reduced carnitine and antiepileptic drugs cause relationship or co-existance. Acta Pediatrica 1995; 84:93-95.
- Panjwani U, Thakur L, Anand JP, Singh SN, Singh SB, Banerjee PK. Effect of L-Carnitine supplementation on endurance exercise in normobaric/normoxic and hypobaric/hypoxic conditions. Wilderness Environ Med 2007; 18:169-176.
- Serban MC, Sahebkar A, Mikhailidis DP, Toth PP, Jones SR, Muntner P et al. Impact of L-Carnitine on plasma lipoprotein(a) concentrations: A systematic review and meta-analysis of randomized controlled trials. Sci Rep 2016; 12:19188:1-11.
- Shimura S, Hasegawa T. Changes of lipid concentrations in liver and serum by administration of carnitine added diets in rats. J Vet Med Sci 1993; 55:845-847.
- Zhang S, Liu Y, Li Q, Dong X, Hu H, Hu R et al. Exercise improved rat metabolism by raising PPAR-α. Int J Sports Med 2011; 32:568-573.
- Karanth J, Jeevaratnam K. Effect of dietary lipid, carnitine and exercise on lipid profile in rat blood, liver and muscle. Indian J Exp Biol 2009; 47:748-53.
- Kim E, Park H, Cha YS. Exercise training and supplementation with carnitine and antioxidants increases carnitine stores, triglyceride utilization, and endurance in exercising rats. J Nutr Sci Vitaminol, Tokyo, 2004; 50:335-343.
- Sachan DS, Hongu N, Johnsen M. Decreasing oxidative stress with choline and carnitine in women. J Am Coll Nutr 2005; 24:172-176.
- Greigh C, Finch KM, Jones DA, Cooper M, Sargeant AJ, Forte CA. The effects of oral supplementation with L-Carnitine on maximum and submaximum exercise capacity. Eur J Appl Physiol Occup Physiol 1987; 56:457-460.
- Mansour HH. Protective role of carnitine ester against radiation-induced oxidative stress in rats. Pharmacol Res 2006; 54:165-171.
- Annadurai T, Vigneshwari S, Thirukumaran R, Thomas PA, Geraldine P. Acetyl-L-Carnitine prevents carbon tetrachloride-induced oxidative stress in various tissues of Wistar rats. J Physiol Biochem 2011; 67:519-530.
- Parandak K, Arazi H, Khoshkhahesh F, Nakhostin-Roohi B. The Effect of Two-Week L-Carnitine Supplementation on Exercise-Induced Oxidative Stress and Muscle Damage. Asian J Sports Med 2014; 5:123-8.
- Åžıktar E, Ekinci D, Åžıktar E, Beydemir Åž, Gülçin ć°, Günay M. Protective role of L-Carnitine supplementation against exhaustive exercise induced oxidative stress in rats. Eur J Pharmacol 2011; 668:407-413.
- Karanth J, Jeevaratnam K. Oxidative stress and antioxidant status in rat blood, liver and muscle: effect of dietary lipid, carnitine and exercise. Int J Vitam Nutr Res 2005; 75:333-339.
- Atalay GN, Erikoglu OG, Sezen BF, Coskun CS. Effects of acute L-Carnitine supplementation on nitric oxide production and oxidative stress after exhaustive exercise in young soccer players. J Sports Med Phys Fitness 2015; 55:9-15.
- Sheng X, Zhang Y, Gong Z, Huang C, Zang YQ. Improved insulin resistance and lipid metabolism by cinnamon extract through activation of peroxisome proliferator-activated receptors. PPAR Res 2008; 2008:581348.
- Grimaldi PA. Regulatory role of peroxisome proliferator-activated receptor delta (PPARδ) in muscle metabolism. A new target for metabolic syndrome treatment?. Biochimie 2005; 87:5-8.
- Tao L, Bei Y, Lin S, Zhang H, Zhou Y, Jiang J et al. Exercise training protects against acute myocardial infarction via improving myocardial energy metabolism and mitochondrial biogenesis. Cell Physiol Biochem 2015; 37:162-175.
- Giorgino F, De Robertis O, Laviola L, Montrone C, Perrini S, McCowen KC et al. The sentrin-conjugating enzyme mUbc9 interacts with GLUT4 and GLUT1 glucose transporters and regulates transporter levels in skeletal muscle cells. Proc Natl Acad Sci U S A 2000; 97:1125-1130.
- Schnedl WJ, Ferber S, Johnson JH, Newgard CB. STZ transport and cytotoxicity: specific enhancement in GLUT2-expressing cells. Diabetes 1994; 43:1326-1333.
- Stenbit AE, Tsao TS, Li J, Burcelin R, Geenen DL, Factor SM et al. GLUT4 heterozygous knockout mice develop muscle insulin resistance and diabetes. Nat Med 1997; 3:1096-1101.
- Sun L, Zeng X, Yan C, Sun X, Gong X, Rao Y et al. Crystal structure of a bacterial homologue of glucose transporters GLUT1-4. Nature 2012; 490: 361-366.
- Kim SH. Effect of exercise on glycose metabolism. J Korean Diabetes 2011; 12:21-4.
- Jeong IG, Oh MJ, Jang MN, Koh YS, Kyle DB, David N et al. Effects of Dietary Caloric Restriction and Exercise on GLUT 2 in Liver and GLUT-4 and VAMP-2 in Muscle Tissue of Diabetic Rats. J Exerc Nutrition Biochem 2009; 13:1-7.
- Lee SS, Seo H, Ryu S, Kwon TD. The effect of swimming exercise and powdered-Salicornia herbacea L. ingestion on glucose metabolism in STZ-induced diabetic rats. J Exerc Nutrition Biochem 2015; 19:235-245.
- Jessen N, Pold R, Buhl ES, Jensen LS, Schmitz O, Lund S. Effects of AICAR and exercise on insulin-stimulated glucose uptake, signaling, and GLUT-4 content in rat muscles. J Appl Physiol 2003; 94:1373-1379.
- Boyda HN, Ramos-Miguel A, Procyshyn RM, Töpfer E, Lant N, Choy HHT et al. Routine exercise ameliorates the metabolic side-effects of treatment with the atypical antipsychotic drug olanzapine in rats. Int J Neuropsychopharmacol 2014; 17:77-90.
- Morato PN, Lollo PC, Moura CS, Batista TM, Camargo RL, Carneiro EM et al. Whey protein hydrolysate increases translocation of GLUT-4 to the plasma membrane independent of insulin in wistar rats. PloS one 2013; 8:1-7.
References
References
Lambertucci RH, Levada-Pires AC, Rossoni LV, Curi R, Pithon-Curi TC. Effects of aerobic exercise training on antioxidant enzyme activities and mRNA levels in soleus muscle from young and aged rats. Mech Ageing Dev 2007;128:267-75.
Powers SK, Jackson MJ. Exercise-induced oxidative stress: cellular mechanisms and impact on muscle force production. Physiol Rev 2008; 88:1243-76.
Sjödin B, HellstenWesting Y, Apple FS. Biochemical mechanisms for oxygen free radical formation during exercise. Sports Med 1990; 10:236-54.
Hartmann A, Niess A. In: Oxidative DNA damage in exercise. Sen C; Packer L; Hanninen O, (eds.), Handbook of oxidants and antioxidants in exercise. Elsevier, Amsterdam, 2000, pp. 195-217
Halliwell B, Gutteridge JMC. Free radicals in biology and medicine., Oxford Univ, New York, 1999.
Young IM, Thomson K. Spinning-induced rhabdomyolysis: a case report. Eur J Emerg Med 2004; 11:358-9.
Crentsil V. Mechanistic contribution of carnitine deficiency to geriatric frailty. Aging Res Rev 2010; 9:265-268.
Li J, Zhang Y, Luan H, Chen X, Han Y, Wang C. L-Carnitine protects human hepatocytes from oxidative stress-induced toxicity through Akt-mediated activation of Nrf2 signaling pathway. Can J Physiol Pharmacol 2016; 94:517-25.
Ronsen O. Supplement use and nutritional habits in norwegion elite athletes. Scand J Med Sci Sports 1999; 9:28-35.
Tashiro K, Kawabata K, Sakurai H, Kurachi S, Sakurai F, Yamanishi K et al. Efficient adenovirus vector-mediated PPAR gamma gene transfer into mouse embryoid bodies promotes adipocyte differentiation. J Gene Med 2008; 10:498-507.
Nicholson AC. Expression of CD36 in macrophages and atherosclerosis: the role of lipid regulation of PPARgamma signaling. Trends Cardiovasc Med 2004;14: 8-12.
Rosenson RS. Effects of peroxisome proliferator-activated receptors on lipoprotein metabolism and glucose control in type 2 diyabetes mellitus. Am J Cardiol 2007; 99:96-104.
Varga T, Nagy L. Nuclear receptors, transcription factors linking lipid metabolism and immunity: the case of peroxisome proliferator-activated receptor gamma. Eur J Clin Invest 2008; 38:695-707.
Cock TA, Houten SM, Auwerx J. Peroxisome proliferator- activated receptor γ :too much of a good thing cause harm. EMBO Rep 2004; 5:142-147.
Yang J, Holman GD. Long-term metformin treatment stimulates cardiomyocyte glucose transport through an AMP-activated protein kinase dependent reduction in GLUT4 endocytosis. Endocrinology 2006; 147:2728-36.
Goodyear LJ, Kahn BB. Exercise glucose transport, and insulin sensitivity. Annu Rev Med 1998; 49:235-61.
Mizock B. Alterations in fuel metabolism in critical illness: hyperglycaemia. Best Pract Res Clin Endocrinol Metab 2001; 15:533-551.
Powers SK, Jackson MJ. Exercise-induced oxidative stress: cellular mechanisms and impact on muscle force production. Physiol Rev 2008; 88:1243-76.
Gülçin ć°. Antioxidant and antiradical activities of L-Carnitine. Life sci 2006; 78:803-811.
Feng Y, Guo C, Weı J, Yang J, Ge Y, Gao L. Necessity of carnitine supplementation in semistarved rats fed a high-fat diet. Nutrition 2001; 7:628-631.
Rani PJ, Panneerselvam C. Protective efficacy of L-Carnitine on acetylcholinesterase activity in aged rat brain. J Gerontol A Biol Sci Med Sci 2001; 56:140-141.
Karatepe M. Simultaneous determination of ascorbic acid and free malondialdehyde in human serum by HPLC-UV. Lc Gc North America 2004; 22:362-365.
Balh JJ, Bressler R. The pharmacology of carnitine. Ann Rev Pharmacol Toxicol 1987; 27:257-77.
Zelnik N, Fridkis S, Gruener N. Reduced carnitine and antiepileptic drugs cause relationship or co-existance. Acta Pediatrica 1995; 84:93-95.
Panjwani U, Thakur L, Anand JP, Singh SN, Singh SB, Banerjee PK. Effect of L-Carnitine supplementation on endurance exercise in normobaric/normoxic and hypobaric/hypoxic conditions. Wilderness Environ Med 2007; 18:169-176.
Serban MC, Sahebkar A, Mikhailidis DP, Toth PP, Jones SR, Muntner P et al. Impact of L-Carnitine on plasma lipoprotein(a) concentrations: A systematic review and meta-analysis of randomized controlled trials. Sci Rep 2016; 12:19188:1-11.
Shimura S, Hasegawa T. Changes of lipid concentrations in liver and serum by administration of carnitine added diets in rats. J Vet Med Sci 1993; 55:845-847.
Zhang S, Liu Y, Li Q, Dong X, Hu H, Hu R et al. Exercise improved rat metabolism by raising PPAR-α. Int J Sports Med 2011; 32:568-573.
Karanth J, Jeevaratnam K. Effect of dietary lipid, carnitine and exercise on lipid profile in rat blood, liver and muscle. Indian J Exp Biol 2009; 47:748-53.
Kim E, Park H, Cha YS. Exercise training and supplementation with carnitine and antioxidants increases carnitine stores, triglyceride utilization, and endurance in exercising rats. J Nutr Sci Vitaminol, Tokyo, 2004; 50:335-343.
Sachan DS, Hongu N, Johnsen M. Decreasing oxidative stress with choline and carnitine in women. J Am Coll Nutr 2005; 24:172-176.
Greigh C, Finch KM, Jones DA, Cooper M, Sargeant AJ, Forte CA. The effects of oral supplementation with L-Carnitine on maximum and submaximum exercise capacity. Eur J Appl Physiol Occup Physiol 1987; 56:457-460.
Mansour HH. Protective role of carnitine ester against radiation-induced oxidative stress in rats. Pharmacol Res 2006; 54:165-171.
Annadurai T, Vigneshwari S, Thirukumaran R, Thomas PA, Geraldine P. Acetyl-L-Carnitine prevents carbon tetrachloride-induced oxidative stress in various tissues of Wistar rats. J Physiol Biochem 2011; 67:519-530.
Parandak K, Arazi H, Khoshkhahesh F, Nakhostin-Roohi B. The Effect of Two-Week L-Carnitine Supplementation on Exercise-Induced Oxidative Stress and Muscle Damage. Asian J Sports Med 2014; 5:123-8.
Åžıktar E, Ekinci D, Åžıktar E, Beydemir Åž, Gülçin ć°, Günay M. Protective role of L-Carnitine supplementation against exhaustive exercise induced oxidative stress in rats. Eur J Pharmacol 2011; 668:407-413.
Karanth J, Jeevaratnam K. Oxidative stress and antioxidant status in rat blood, liver and muscle: effect of dietary lipid, carnitine and exercise. Int J Vitam Nutr Res 2005; 75:333-339.
Atalay GN, Erikoglu OG, Sezen BF, Coskun CS. Effects of acute L-Carnitine supplementation on nitric oxide production and oxidative stress after exhaustive exercise in young soccer players. J Sports Med Phys Fitness 2015; 55:9-15.
Sheng X, Zhang Y, Gong Z, Huang C, Zang YQ. Improved insulin resistance and lipid metabolism by cinnamon extract through activation of peroxisome proliferator-activated receptors. PPAR Res 2008; 2008:581348.
Grimaldi PA. Regulatory role of peroxisome proliferator-activated receptor delta (PPARδ) in muscle metabolism. A new target for metabolic syndrome treatment?. Biochimie 2005; 87:5-8.
Tao L, Bei Y, Lin S, Zhang H, Zhou Y, Jiang J et al. Exercise training protects against acute myocardial infarction via improving myocardial energy metabolism and mitochondrial biogenesis. Cell Physiol Biochem 2015; 37:162-175.
Giorgino F, De Robertis O, Laviola L, Montrone C, Perrini S, McCowen KC et al. The sentrin-conjugating enzyme mUbc9 interacts with GLUT4 and GLUT1 glucose transporters and regulates transporter levels in skeletal muscle cells. Proc Natl Acad Sci U S A 2000; 97:1125-1130.
Schnedl WJ, Ferber S, Johnson JH, Newgard CB. STZ transport and cytotoxicity: specific enhancement in GLUT2-expressing cells. Diabetes 1994; 43:1326-1333.
Stenbit AE, Tsao TS, Li J, Burcelin R, Geenen DL, Factor SM et al. GLUT4 heterozygous knockout mice develop muscle insulin resistance and diabetes. Nat Med 1997; 3:1096-1101.
Sun L, Zeng X, Yan C, Sun X, Gong X, Rao Y et al. Crystal structure of a bacterial homologue of glucose transporters GLUT1-4. Nature 2012; 490: 361-366.
Kim SH. Effect of exercise on glycose metabolism. J Korean Diabetes 2011; 12:21-4.
Jeong IG, Oh MJ, Jang MN, Koh YS, Kyle DB, David N et al. Effects of Dietary Caloric Restriction and Exercise on GLUT 2 in Liver and GLUT-4 and VAMP-2 in Muscle Tissue of Diabetic Rats. J Exerc Nutrition Biochem 2009; 13:1-7.
Lee SS, Seo H, Ryu S, Kwon TD. The effect of swimming exercise and powdered-Salicornia herbacea L. ingestion on glucose metabolism in STZ-induced diabetic rats. J Exerc Nutrition Biochem 2015; 19:235-245.
Jessen N, Pold R, Buhl ES, Jensen LS, Schmitz O, Lund S. Effects of AICAR and exercise on insulin-stimulated glucose uptake, signaling, and GLUT-4 content in rat muscles. J Appl Physiol 2003; 94:1373-1379.
Boyda HN, Ramos-Miguel A, Procyshyn RM, Töpfer E, Lant N, Choy HHT et al. Routine exercise ameliorates the metabolic side-effects of treatment with the atypical antipsychotic drug olanzapine in rats. Int J Neuropsychopharmacol 2014; 17:77-90.
Morato PN, Lollo PC, Moura CS, Batista TM, Camargo RL, Carneiro EM et al. Whey protein hydrolysate increases translocation of GLUT-4 to the plasma membrane independent of insulin in wistar rats. PloS one 2013; 8:1-7.