Effects of high-fat diet and physical activity on pyruvate dehydrogenase kinase-4 in mouse skeletal muscle

Nutrition & Metabolism

Heikki Kainulainen²  Hilkka Reunanen¹  Riikka Kivelä²  Maarit Lehti³  Juha J Hulmi²  Sira Torvinen²  Mika Silvennoinen²  Rita Rinnankoski-Tuikka² 

[1] Department of Biological and Environmental Sciences, University of Jyväskylä, Jyväskylä, Finland;Neuromuscular Research Center, Department of Biology of Physical Activity, University of Jyväskylä, Jyväskylä, Finland;LIKES Research Center for Sport and Health Sciences, University of Jyväskylä, Jyväskylä, Finland

关键词: Fuel switching;    Glucose;    Lipids;    Mitochondria;    Skeletal muscle;   

Others  :  815285
DOI  :  10.1186/1743-7075-9-53

 received in 2012-03-21, accepted in 2012-06-09,  发布年份 2012

【 摘 要 】

Background

The expression of PDK4 is elevated by diabetes, fasting and other conditions associated with the switch from the utilization of glucose to fatty acids as an energy source. It is previously shown that peroxisome proliferator-activated receptor γ coactivator 1α (PGC-1α), a master regulator of energy metabolism, coactivates in cell lines pyruvate dehydrogenase kinase-4 (PDK4) gene expression via the estrogen-related receptor α (ERRα). We investigated the effects of long-term high-fat diet and physical activity on the expression of PDK4, PGC-1α and ERRα and the amount and function of mitochondria in skeletal muscle.

Methods

Insulin resistance was induced by a high-fat (HF) diet for 19 weeks in C57BL/6 J mice, which were either sedentary or with access to running wheels. The skeletal muscle expression levels of PDK4, PGC-1α and ERRα were measured and the quality and quantity of mitochondrial function was assessed.

Results

The HF mice were more insulin-resistant than the low-fat (LF) -fed mice. Upregulation of PDK4 and ERRα mRNA and protein levels were seen after the HF diet, and when combined with running even more profound effects on the mRNA expression levels were observed. Chronic HF feeding and voluntary running did not have significant effects on PGC-1α mRNA or protein levels. No remarkable difference was found in the amount or function of mitochondria.

Conclusions

Our results support the view that insulin resistance is not mediated by the decreased qualitative or quantitative properties of mitochondria. Instead, the role of PDK4 should be contemplated as a possible contributor to high-fat diet-induced insulin resistance.

【 授权许可】

   
2012 Rinnankoski-Tuikka et al.; licensee BioMed Central Ltd.

【 图 表 】

Figure 1.

Figure 2.

Figure 3.

Figure 4.

Figure 5.

Figure 6.

Figure 7.

【 参考文献 】

• [1]Kelley DE, He J, Menshikova EV, Ritov VB: Dysfunction of mitochondria in human skeletal muscle in type 2 diabetes. Diabetes 2002, 51:2944-2950.
• [2]Schrauwen-Hinderling VB, Kooi ME, Hesselink MK, Jeneson JA, Backes WH, van Echteld CJ, van Engelshoven JM, Mensink M, Schrauwen P: Impaired in vivo mitochondrial function but similar intramyocellular lipid content in patientswith type 2 diabetes mellitus and BMI-matched control subjects. Diabetologia 2007, 50:113-120.
• [3]Asmann YW, Stump CS, Short KR, Coenen-Schimke JM, Guo Z, Bigelow ML, Nair KS: Skeletal muscle mitochondrial functions, mitochondrial DNA copy numbers, and gene transcript profiles in type 2 diabetic and nondiabetic subjects at equal levels of low or high insulin and euglycemia. Diabetes 2006, 55:3309-3319.
• [4]Bonnard C, Durand A, Peyrol S, Chanseaume E, Chauvin MA, Morio B, Vidal H, Rieusset J: Mitochondrial dysfunction results from oxidative stress in the skeletal muscle of diet-induced insulin-resistant mice. J Clin Investig 2008, 118:789-800.
• [5]Mootha VK, Lindgren CM, Eriksson KF, Subramanian A, Sihag S, Lehar J, Puigserver P, Carlsson E, Ridderstrale M, Laurila E, Houstis N, Daly MJ, Patterso N, Mesirov JP, Golub TR, Tamayo P, Spiegelman B, Lander ES, Hirschhorn JN, Altshuler D, Groop LC: PGC-1alpha-responsive genes involved in oxidative phosphorylation are coordinately downregulated in human diabetes. Nat Genet 2003, 34:267-273.
• [6]Petersen KF, Dufour S, Befroy D, Garcia R, Shulman GI: Impaired mitochondrial activity in the insulin-resistant offspring of patients with type 2 diabetes. N Engl J Med 2004, 350:664-671.
• [7]Ritov VB, Menshikova EV, He J, Ferrell RE, Goodpaster BH, Kelley DE: Deficiency of subsarcolemmal mitochondria in obesity and type 2 diabetes. Diabetes 2005, 54:8-14.
• [8]Sparks LM, Xie H, Koza RA, Mynatt R, Hulver MW, Bray GA, Smith SR: A high- fat diet coordinately downregulates genes required for mitochondrial oxidative phosphorylation in skeletal muscle. Diabetes 2005, 54:1926-1933.
• [9]Lowell BB, Shulman GI: Mitochondrial dysfunction and type 2 diabetes. Science 2005, 307:384-387.
• [10]Morino K, Petersen KF, Shulman GI: Molecular mechanisms of insulin resistance in humans and their potential links with mitochondrial dysfunction. Diabetes 2006, 55(Suppl 2):S9-S15.
• [11]Garcia-Roves P, Huss JM, Han DH, Hancock CR, Iglesias-Gutierrez E, Chen M, Holloszy JO: Raising plasma fatty acid concentration induces increased biogenesis of mitochondria in skeletal muscle. Proc Natl Acad Sci U S A 2007, 104:10709-10713.
• [12]Hancock CR, Han DH, Chen M, Terada S, Yasuda T, Wright DC, Holloszy JO: High-fat diets cause insulin resistance despite an increase in muscle mitochondria. Proc Natl Acad Sci U S A 2008, 105:7815-7820.
• [13]Turner N, Bruce CR, Beale SM, Hoehn KL, So T, Rolph MS, Cooney GJ: 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.
• [14]Koves TR, Li P, An J, Akimoto T, Slentz D, Ilkayeva O, Dohm GL, Yan Z, Newgard CB, Muoio DM: Peroxisome proliferator-activated receptor-gamma co- activator 1alpha-mediated metabolic remodeling of skeletal myocytes mimics exercise training and reverses lipid-induced mitochondrial inefficiency. J Biol Chem 2005, 280:33588-33598.
• [15]Han DH, Hancock CR, Jung SR, Higashida K, Kim SH, Holloszy JO: Deficiency of the mitochondrial electron transport chain in muscle does not cause insulin resistance. PLoS One 2011, 6:e19739.
• [16]Hegarty BD, Turner N, Cooney GJ, Kraegen EW: Insulin resistance and fuel homeostasis: the role of AMP-activated protein kinase. Acta Physiol (Oxf) 2009, 196:129-145.
• [17]Holloszy JO: Skeletal muscle "mitochondrial deficiency" does not mediate insulin resistance. Am J Clin Nutr 2009, 89:463S-466S.
• [18]Toledo FG, Menshikova EV, Ritov VB, Azuma K, Radikova Z, DeLany J, Kelley DE: Effects of physical activity and weight loss on skeletal muscle mitochondria and relationship with glucose control in type 2 diabetes. Diabetes 2007, 56:2142-2147.
• [19]Goodpaster BH, Brown NF: Skeletal muscle lipid and its association with insulin resistance: what is the role for exercise? Exerc Sport Sci Rev 2005, 33:150-154.
• [20]van Aggel-Leijssen DP, Saris WH, Wagenmakers AJ, Senden JM, van Baak MA: Effect of exercise training at different intensities on fat metabolism of obese men. J Appl Physiol 2002, 92:1300-1309.
• [21]Benton CR, Wright DC, Bonen A: PGC-1alpha-mediated regulation of gene expression and metabolism: implications for nutrition and exercise prescriptions. Appl Physiol Nutr Metab 2008, 33:843-862.
• [22]Handschin C, Rhee J, Lin J, Tarr PT, Spiegelman BM: An autoregulatory loop controls peroxisome proliferator-activated receptor gamma coactivator 1alpha expression in muscle. Proc Natl Acad Sci U S A 2003, 100:7111-7116.
• [23]Mootha VK, Handschin C, Arlow D, Xie X, St Pierre J, Sihag S, Yang W, Altshuler D, Puigserver P, Patterson N, Willy PJ, Schulman IG, Heyman RA, Lander ES, Spiegelman BM: Erralpha and Gabpa/b specify PGC-1alpha-dependent oxidative phosphorylation gene expression that is altered in diabetic muscle. Proc Natl Acad Sci U S A 2004, 101:6570-6575.
• [24]Schreiber SN, Emter R, Hock MB, Knutti D, Cardenas J, Podvinec M, Oakeley EJ, Kralli A: The estrogen-related receptor alpha (ERRalpha) functions in PPARgamma coactivator 1alpha (PGC-1alpha)-induced mitochondrial biogenesis. Proc Natl Acad Sci U S A 2004, 101:6472-6477.
• [25]Wu P, Inskeep K, Bowker-Kinley MM, Popov KM, Harris RA: Mechanism responsible for inactivation of skeletal muscle pyruvate dehydrogenase complex in starvation and diabetes. Diabetes 1999, 48:1593-1599.
• [26]Pilegaard H, Saltin B, Neufer PD: Exercise induces transient transcriptional activation of the PGC-1alpha gene in human skeletal muscle. J Physiol 2003, 546:851-858.
• [27]Akimoto T, Pohnert SC, Li P, Zhang M, Gumbs C, Rosenberg PB, Williams RS, Yan Z: Exercise stimulates Pgc-1alpha transcription in skeletal muscle through activation of the p38 MAPK pathway. J Biol Chem 2005, 280:19587-19593.
• [28]Wright DC, Han DH, Garcia-Roves PM, Geiger PC, Jones TE, Holloszy JO: Exercise-induced mitochondrial biogenesis begins before the increase in muscle PGC-1alpha expression. J Biol Chem 2007, 282:194-199.
• [29]Baar K, Wende AR, Jones TE, Marison M, Nolte LA, Chen M, Kelly DP, Holloszy JO: Adaptations of skeletal muscle to exercise: rapid increase in the transcriptional coactivator PGC-1. FASEB J 2002, 16:1879-1886.
• [30]Terada S, Goto M, Kato M, Kawanaka K, Shimokawa T, Tabata I: Effects of low- intensity prolonged exercise on PGC-1 mRNA expression in rat epitrochlearis muscle. Biochem Biophys Res Commun 2002, 296:350-354.
• [31]Wende AR, Huss JM, Schaeffer PJ, Giguere V, Kelly DP: PGC-1alpha coactivates PDK4 gene expression via the orphan nuclear receptor ERRalpha: a mechanism for transcriptional control of muscle glucose metabolism. Mol Cell Biol 2005, 25:10684-10694.
• [32]Connaughton S, Chowdhury F, Attia RR, Song S, Zhang Y, Elam MB, Cook GA, Park EA: Regulation of pyruvate dehydrogenase kinase isoform 4 (PDK4) gene expression by glucocorticoids and insulin. Mol Cell Endocrinol 2010, 315:159-167.
• [33]Feige JN, Auwerx J: Transcriptional coregulators in the control of energy homeostasis. Trends Cell Biol 2007, 17:292-301.
• [34]Kiilerich K, Gudmundsson M, Birk JB, Lundby C, Taudorf S, Plomgaard P, Saltin B, Pedersen PA, Wojtaszewski JF, Pilegaard H: Low muscle glycogen and elevated plasma free fatty acid modify but do not prevent exercise-induced PDH activation in human skeletal muscle. Diabetes 2010, 59:26-32.
• [35]Majer M, Popov KM, Harris RA, Bogardus C, Prochazka M: Insulin downregulates pyruvate dehydrogenase kinase (PDK) mRNA: potential mechanism contributing to increased lipid oxidation in insulin-resistant subjects. Mol Genet Metab 1998, 65:181-186.
• [36]Pilegaard H, Neufer PD: Transcriptional regulation of pyruvate dehydrogenase kinase 4 in skeletal muscle during and after exercise. Proc Nutr Soc 2004, 63:221-226.
• [37]Araki M, Motojima K: Identification of ERRalpha as a specific partner of PGC-1alpha for the activation of PDK4 gene expression in muscle. FEBS J 2006, 273:1669-1680.
• [38]Zhang Y, Ma K, Sadana P, Chowdhury F, Gaillard S, Wang F, McDonnell DP, Unterman TG, Elam MB, Park EA: Estrogen-related receptors stimulate pyruvate dehydrogenase kinase isoform 4 gene expression. J Biol Chem 2006, 281:39897-39906.
• [39]Ma H, Torvinen S, Silvennoinen M, Rinnankoski-Tuikka R, Kainulainen H, Morko J, Peng Z, Kujala UM, Rahkila P, Suominen H: Effects of diet-induced obesity and voluntary wheel running on bone properties in young male C57BL/6 J mice. Calcif Tissue Int 2010, 86:411-419.
• [40]Lundby C, Nordsborg N, Kusuhara K, Kristensen KM, Neufer PD, Pilegaard H: Gene expression in human skeletal muscle: alternative normalization method and effect of repeated biopsies. Eur J Appl Physiol 2005, 95:351-360.
• [41]Hulmi JJ, Tannerstedt J, Selanne H, Kainulainen H, Kovanen V, Mero AA: Resistance exercise with whey protein ingestion affects mTOR signaling pathway and myostatin in men. J Appl Physiol 2009, 106:1720-1729.
• [42]Hulmi JJ, Silvennoinen M, Lehti M, Kivela R, Kainulainen H: Altered REDD1, myostatin, and Akt/mTOR/FoxO/MAPK signaling in streptozotocin-induced diabetic muscle atrophy. Am J Physiol Endocrinol Metab 2012, 302:E307-E315.
• [43]Pette D, Tyler KR: Response of succinate dehydrogenase activity in fibres of rabbit tibialis anterior muscle to chronic nerve stimulation. J Physiol 1983, 338:1-9.
• [44]Wardlaw GM, Kaplan ML: Oxygen consumption and oxidative capacity of muscles from young obese and nonobese Zucker rats. Am J Physiol 1984, 247:R911-R917.
• [45]Spiegelman BM: Transcriptional control of energy homeostasis through the PGC1 coactivators. Novartis Found Symp 2007, 286:196-203. 3–6; discusssion 6–12, 162–3
• [46]Sugden MC, Holness MJ: Mechanisms underlying regulation of the expression and activities of the mammalian pyruvate dehydrogenase kinases. Arch Physiol Biochem 2006, 112:139-149.
• [47]Chokkalingam K, Jewell K, Norton L, Littlewood J, van Loon LJ, Mansell P, Macdonald IA, Tsintzas K: High-fat/low carbohydrate diet reduces insulin- stimulated carbohydrate oxidation but stimulates nonoxidative glucose disposal in humans: An important role for skeletal muscle pyruvate dehydrogenase kinase 4. J Clin Endocrinol Metab 2007, 92:284-292.
• [48]Holness MJ, Kraus A, Harris RA, Sugden MC: Targeted upregulation of pyruvate dehydrogenase kinase (PDK)-4 in slow-twitch skeletal muscle underlies the stable modification of the regulatory characteristics of PDK induced by high- fat feeding. Diabetes 2000, 49:775-781.
• [49]Hoy AJ, Brandon AE, Turner N, Watt MJ, Bruce CR, Cooney GJ, Kraegen EW: Lipid and insulin infusion-induced skeletal muscle insulin resistance is likely due to metabolic feedback and not changes in IRS-1, Akt, or AS160 phosphorylation. Am J Physiol Endocrinol Metab 2009, 297:E67-E75.
• [50]Jager S, Handschin C, St-Pierre J, Spiegelman BM: AMP-activated protein kinase (AMPK) action in skeletal muscle via direct phosphorylation of PGC-1alpha. Proc Natl Acad Sci U S A 2007, 104:12017-12022.
• [51]Wu Z, Puigserver P, Andersson U, Zhang C, Adelmant G, Mootha V, Troy A, Cinti S, Lowell B, Scarpulla RC, Spiegelman BM: Mechanisms controlling mitochondrial biogenesis and respiration through the thermogenic coactivator PGC-1. Cell 1999, 98:115-124.
• [52]Crunkhorn S, Dearie F, Mantzoros C, Gami H, da Silva WS, Espinoza D, Faucette R, Barry K, Bianco AC, Patti ME: Peroxisome proliferator activator receptor gamma coactivator-1 expression is reduced in obesity: potential pathogenic role of saturated fatty acids and p38 mitogen-activated protein kinase activation. J Biol Chem 2007, 282:15439-15450.
• [53]Rodriguez AM, Sanchez J, Tobaruela A, Priego T, Pico C, Palou A: Time-course effects of increased fatty acid supply on the expression of genes involved in lipid/glucose metabolism in muscle cells. Cell Physiol Biochem 2010, 25:337-346.
• [54]Luo J, Sladek R, Carrier J, Bader JA, Richard D, Giguere V: Reduced fat mass in mice lacking orphan nuclear receptor estrogen-related receptor alpha. Mol Cell Biol 2003, 23:7947-7956.
• [55]Sladek R, Bader JA, Giguere V: The orphan nuclear receptor estrogen-related receptor alpha is a transcriptional regulator of the human medium-chain acyl coenzyme A dehydrogenase gene. Mol Cell Biol 1997, 17:5400-5409.
• [56]Fernandez-Marcos PJ, Auwerx J, Giguere V: Regulation of PGC-1alpha, a nodal regulator of mitochondrial biogenesis. Am J Clin Nutr 2001., 93
• [57]Bjursell M, Gerdin AK, Lelliott CJ, Egecioglu E, Elmgren A, Tornell J, Oscarsson J, Bohlooly-Y M: Acutely reduced locomotor activity is a major contributor to Western diet-induced obesity in mice. Am J Physiol Endocrinol Metab 2008, 294:E251-E260.
• [58]Novak CM, Kotz CM, Levine JA: Central orexin sensitivity, physical activity, and obesity in diet-induced obese and diet resistant rats. Am J Physiol Endocrinol Metab 2006, 290:E396-E403.
• [59]Novak CM, Burghardt PR, Levine JA: The use of a running wheel to measure activity in rodents: relationship to energy balance, general activity, and reward. Neurosci Biobehav Rev 2012, 36:1001-1014.
• [60]Han DH, Hansen PA, Host HH, Holloszy JO: Insulin resistance of muscle glucose transport in rats fed a high-fat diet: a reevaluation. Diabetes 1997, 46:1761-1767.
• [61]Roche TE, Hiromasa Y: Pyruvate dehydrogenase kinase regulatory mechanisms and inhibition in treating diabetes, heart ischemia, and cancer. Cell Mol Life Sci 2007, 64:830-849.
• [62]Wu P, Blair PV, Sato J, Jaskiewicz J, Popov KM, Harris RA: Starvation increases the amount of pyruvate dehydrogenase kinase in several mammalian tissues. Arch Biochem Biophys 2000, 381:1-7.
• [63]Han DH, Hancock C, Jung SR, Holloszy JO: Is “fat-induced” muscle insulin resistance rapidly reversible? Am J Physiol Endocrinol Metab 2009, 297:E236-E241.
• [64]Ikonen E, Vainio S: Lipid microdomains and insulin resistance: is there a connection. Science's STKE 2005, 2005:pe3.
• [65]Galuska D, Ryder J, Kawano Y, Charron MJ, Zierath JR: Insulin signaling and glucose transport in insulin resistant skeletal muscle. Special reference to GLUT4 transgenic and GLUT4 knockout mice. Adv Exp Med Biol 1998, 441:73-85.
• [66]Coll T, Jove M, Rodriguez-Calvo R, Eyre E, Palomer X, Sanchez RM, Merlos M, Laguna JC, Vazquez-Carrera M: Palmitate mediated downregulation of peroxisome proliferator-activated receptor-gamma coactivator 1alpha in skeletal muscle cells involves MEK1/2 and nuclear factor-kappaB activation. Diabetes 2006, 55:2779-2787.