Mitochondrial biogenesis and PGC-1α deacetylation by chronic treadmill exercise: differential response in cardiac and skeletal muscle
Tóm tắt
Posttranslational modifications of the transcriptional coactivator PGC-1α by the deacetylase SIRT1 and the kinase AMPK are involved in exercise-induced mitochondrial biogenesis in skeletal muscle. However, similar investigations have not been performed in the left ventricle (LV). Here, we tested whether treadmill training (12 weeks) modifies PGC-1α and mitochondrial biogenesis in gastrocnemius muscle and LV of C57BL/6 J wild-type mice and IL-6-deficient mice with a reported impairment in muscular AMPK activation similarly. Physical activity lowered the plasma insulin and glucose in both mouse strains, suggesting improved insulin sensitivity. The gastrocnemius muscle of IL-6-deficient mice showed reduced mitochondrial respiration and enzyme activity, which was partially normalized after training. Chronic exercise enhanced the mitochondrial biogenesis in gastrocnemius muscle as indicated by increased mRNA or protein expression of primary mitochondrial transcripts, higher mtDNA content and increased citrate synthase activity. Parallel to these changes, we observed AMPK activation, SIRT1 induction and PGC-1α deacetylation. Chronic treadmill training resulted in a mild cardiac hypertrophy in both mouse strains. However, none of these changes observed in skeletal muscle were detected in the LV (both mouse strains) with the exception of AMPK activation and a mildly increased succinate-dependent respiration. Thus, chronic endurance training induces a sustained mitochondrial biogenic response in mouse gastrocnemius muscle but not in the LV. Although AMPK activation occurs in both muscular organs, the absence of SIRT1-dependent PGC-1α deacetylation may be responsible for this significant difference. AMPK activation by IL-6 appears to be dispensable for the mitochondrial biogenic responses to chronic treadmill exercise.
Tài liệu tham khảo
Arany Z, He H, Lin J, Hoyer K, Handschin C, Toka O, Ahmad F, Matsui T, Chin S, Wu PH, Rybkin II, Shelton JM, Manieri M, Cinti S, Schoen FJ, Bassel-Duby R, Rosenzweig A, Ingwall JS, Spiegelman BM (2005) Transcriptional coactivator PGC-1 alpha controls the energy state and contractile function of cardiac muscle. Cell Metab 1:259–271. doi:S1550-4131(05)00081-1
Banerjee I, Fuseler JW, Intwala AR, Baudino TA (2009) IL-6 loss causes ventricular dysfunction, fibrosis, reduced capillary density, and dramatically alters the cell populations of the developing and adult heart. Am J Physiol Heart Circ Physiol 296:H1694–H1704. doi:00908.2008
Bilet L, van de Weijer T, Hesselink MK, Glatz JF, Lamb HJ, Wildberger J, Kooi ME, Schrauwen P, Schrauwen-Hinderling VB (2011) Exercise-induced modulation of cardiac lipid content in healthy lean young men. Basic Res Cardiol 106:307–315. doi:10.1007/s00395-010-0144-x
Boengler K, Hilfiker-Kleiner D, Drexler H, Heusch G, Schulz R (2008) The myocardial JAK/STAT pathway: from protection to failure. Pharmacol Ther 120:172–185. doi:S0163-7258(08)00140-X
Boengler K, Konietzka I, Buechert A, Heinen Y, Garcia-Dorado D, Heusch G, Schulz R (2007) Loss of ischemic preconditioning’s cardioprotection in aged mouse hearts is associated with reduced gap junctional and mitochondrial levels of connexin 43. Am J Physiol Heart Circ Physiol 292:H1764–H1769. doi:01071.2006[
Boengler K, Schulz R, Heusch G (2009) Loss of cardioprotection with ageing. Cardiovasc Res 83:247–261. doi:cvp033
Boveris A, Navarro A (2008) Systemic and mitochondrial adaptive responses to moderate exercise in rodents. Free Radic Biol Med 44:224–229. doi:S0891-5849(07)00584-9
Canto C, Gerhart-Hines Z, Feige JN, Lagouge M, Noriega L, Milne JC, Elliott PJ, Puigserver P, Auwerx J (2009) AMPK regulates energy expenditure by modulating NAD+ metabolism and SIRT1 activity. Nature 458:1056–1060. doi:nature07813
Cimen H, Han MJ, Yang Y, Tong Q, Koc H, Koc EC (2010) Regulation of succinate dehydrogenase activity by SIRT3 in mammalian mitochondria. Biochemistry 49:304–311. doi:10.1021/bi901627u
Cole MA, Murray AJ, Cochlin LE, Heather LC, McAleese S, Knight NS, Sutton E, Jamil AA, Parassol N, Clarke K (2011) A high fat diet increases mitochondrial fatty acid oxidation and uncoupling to decrease efficiency in rat heart. Basic Res Cardiol 106:447–457. doi:10.1007/s00395-011-0156-1
Di Gregorio GB, Hensley L, Lu T, Ranganathan G, Kern PA (2004) Lipid and carbohydrate metabolism in mice with a targeted mutation in the IL-6 gene: absence of development of age-related obesity. Am J Physiol Endocrinol Metab 287:E182–E187. doi:10.1152/ajpendo.00189.2003
Eisele JC, Schaefer IM, Randel Nyengaard J, Post H, Liebetanz D, Bruel A, Muhlfeld C (2008) Effect of voluntary exercise on number and volume of cardiomyocytes and their mitochondria in the mouse left ventricle. Basic Res Cardiol 103:12–21. doi:10.1007/s00395-007-0684-x
Faldt J, Wernstedt I, Fitzgerald SM, Wallenius K, Bergstrom G, Jansson JO (2004) Reduced exercise endurance in interleukin-6-deficient mice. Endocrinology 145:2680–2686. doi:10.1210/en.2003-1319
Ferrara N, Rinaldi B, Corbi G, Conti V, Stiuso P, Boccuti S, Rengo G, Rossi F, Filippelli A (2008) Exercise training promotes SIRT1 activity in aged rats. Rejuvenation Res 11:139–150. doi:10.1089/rej.2007.0576
Finck BN, Kelly DP (2007) Peroxisome proliferator-activated receptor gamma coactivator-1 (PGC-1) regulatory cascade in cardiac physiology and disease. Circulation 115:2540–2548. doi:115/19/2540
Fuchs M, Hilfiker A, Kaminski K, Hilfiker-Kleiner D, Guener Z, Klein G, Podewski E, Schieffer B, Rose-John S, Drexler H (2003) Role of interleukin-6 for LV remodeling and survival after experimental myocardial infarction. Faseb J 17:2118–2120. doi:10.1096/fj.03-0331fje
Fulco M, Schiltz RL, Iezzi S, King MT, Zhao P, Kashiwaya Y, Hoffman E, Veech RL, Sartorelli V (2003) Sir2 regulates skeletal muscle differentiation as a potential sensor of the redox state. Mol Cell 12:51–62. doi:S1097276503002260
Geiger PC, Hancock C, Wright DC, Han DH, Holloszy JO (2007) IL-6 increases muscle insulin sensitivity only at superphysiological levels. Am J Physiol Endocrinol Metab 292:E1842–E1846. doi:00701.2006
Gellerich FN, Deschauer M, Chen Y, Muller T, Neudecker S, Zierz S (2002) Mitochondrial respiratory rates and activities of respiratory chain complexes correlate linearly with heteroplasmy of deleted mtDNA without threshold and independently of deletion size. Biochim Biophys Acta 1556:41–52. doi:S0005272802003055
Gerhart-Hines Z, Rodgers JT, Bare O, Lerin C, Kim SH, Mostoslavsky R, Alt FW, Wu Z, Puigserver P (2007) Metabolic control of muscle mitochondrial function and fatty acid oxidation through SIRT1/PGC-1alpha. EMBO J 26:1913–1923. doi:7601633
Gottlieb RA, Finley KD, Mentzer RM Jr (2009) Cardioprotection requires taking out the trash. Basic Res Cardiol 104:169–180. doi:10.1007/s00395-009-0011-9
Huey KA, Meador BM (2008) Contribution of IL-6 to the Hsp72, Hsp25, and alphaB-crystallin [corrected] responses to inflammation and exercise training in mouse skeletal and cardiac muscle. J Appl Physiol 105:1830–1836. doi:90955.2008
Ikeda S, Kawamoto H, Kasaoka K, Hitomi Y, Kizaki T, Sankai Y, Ohno H, Haga S, Takemasa T (2006) Muscle type-specific response of PGC-1 alpha and oxidative enzymes during voluntary wheel running in mouse skeletal muscle. Acta Physiol (Oxf) 188:217–223. doi:APS1623
Irrcher I, Adhihetty PJ, Joseph AM, Ljubicic V, Hood DA (2003) Regulation of mitochondrial biogenesis in muscle by endurance exercise. Sports Med 33:783–793. doi:33111
Iwabu M, Yamauchi T, Okada-Iwabu M, Sato K, Nakagawa T, Funata M, Yamaguchi M, Namiki S, Nakayama R, Tabata M, Ogata H, Kubota N, Takamoto I, Hayashi YK, Yamauchi N, Waki H, Fukayama M, Nishino I, Tokuyama K, Ueki K, Oike Y, Ishii S, Hirose K, Shimizu T, Touhara K, Kadowaki T (2010) Adiponectin and AdipoR1 regulate PGC-1alpha and mitochondria by Ca(2+) and AMPK/SIRT1. Nature 464:1313–1319. doi:nature08991
Jager S, Handschin C, St-Pierre J, Spiegelman BM (2007) AMP-activated protein kinase (AMPK) action in skeletal muscle via direct phosphorylation of PGC-1alpha. Proc Natl Acad Sci U S A 104:12017–12022. doi:0705070104
Judge S, Jang YM, Smith A, Selman C, Phillips T, Speakman JR, Hagen T, Leeuwenburgh C (2005) Exercise by lifelong voluntary wheel running reduces subsarcolemmal and interfibrillar mitochondrial hydrogen peroxide production in the heart. Am J Physiol Regul Integr Comp Physiol 289:R1564–R1572. doi:00396.2005
Kaminski KA, Oledzka E, Bialobrzewska K, Kozuch M, Musial WJ, Winnicka MM (2007) The effects of moderate physical exercise on cardiac hypertrophy in interleukin 6 deficient mice. Adv Med Sci 52:164–168
Kelly M, Keller C, Avilucea PR, Keller P, Luo Z, Xiang X, Giralt M, Hidalgo J, Saha AK, Pedersen BK, Ruderman NB (2004) AMPK activity is diminished in tissues of IL-6 knockout mice: the effect of exercise. Biochem Biophys Res Commun 320:449–454. doi:10.1016/j.bbrc.2004.05.188
Kong X, Wang R, Xue Y, Liu X, Zhang H, Chen Y, Fang F, Chang Y (2010) Sirtuin 3, a new target of PGC-1alpha, plays an important role in the suppression of ROS and mitochondrial biogenesis. PLoS One 5:e11707. doi:10.1371/journal.pone.0011707
Lagouge M, Argmann C, Gerhart-Hines Z, Meziane H, Lerin C, Daussin F, Messadeq N, Milne J, Lambert P, Elliott P, Geny B, Laakso M, Puigserver P, Auwerx J (2006) Resveratrol improves mitochondrial function and protects against metabolic disease by activating SIRT1 and PGC-1alpha. Cell 127:1109–1122. doi:S0092-8674(06)01428-0
Lehman JJ, Barger PM, Kovacs A, Saffitz JE, Medeiros DM, Kelly DP (2000) Peroxisome proliferator-activated receptor gamma coactivator-1 promotes cardiac mitochondrial biogenesis. J Clin Invest 106:847–856. doi:10.1172/JCI10268
Leone TC, Lehman JJ, Finck BN, Schaeffer PJ, Wende AR, Boudina S, Courtois M, Wozniak DF, Sambandam N, Bernal-Mizrachi C, Chen Z, Holloszy JO, Medeiros DM, Schmidt RE, Saffitz JE, Abel ED, Semenkovich CF, Kelly DP (2005) PGC-1alpha deficiency causes multi-system energy metabolic derangements: muscle dysfunction, abnormal weight control and hepatic steatosis. PLoS Biol 3:e101. doi:04-PLBI-RA-0782R2
Li L, Pan R, Li R, Niemann B, Aurich AC, Chen Y, Rohrbach S (2011) Mitochondrial biogenesis and peroxisome proliferator-activated receptor-gamma coactivator-1alpha (PGC-1alpha) deacetylation by physical activity: intact adipocytokine signaling is required. Diabetes 60:157–167. doi:db10-0331
Lin J, Wu H, Tarr PT, Zhang CY, Wu Z, Boss O, Michael LF, Puigserver P, Isotani E, Olson EN, Lowell BB, Bassel-Duby R, Spiegelman BM (2002) Transcriptional co-activator PGC-1 alpha drives the formation of slow-twitch muscle fibres. Nature 418:797–801. doi:10.1038/nature00904
Lombard DB, Alt FW, Cheng HL, Bunkenborg J, Streeper RS, Mostoslavsky R, Kim J, Yancopoulos G, Valenzuela D, Murphy A, Yang Y, Chen Y, Hirschey MD, Bronson RT, Haigis M, Guarente LP, Farese RV Jr, Weissman S, Verdin E, Schwer B (2007) Mammalian Sir2 homolog SIRT3 regulates global mitochondrial lysine acetylation. Mol Cell Biol 27:8807–8814. doi:MCB.01636-07
Lopez-Lluch G, Hunt N, Jones B, Zhu M, Jamieson H, Hilmer S, Cascajo MV, Allard J, Ingram DK, Navas P, de Cabo R (2006) Calorie restriction induces mitochondrial biogenesis and bioenergetic efficiency. Proc Natl Acad Sci U S A 103:1768–1773. doi:0510452103
Matsakas A, Bozzo C, Cacciani N, Caliaro F, Reggiani C, Mascarello F, Patruno M (2006) Effect of swimming on myostatin expression in white and red gastrocnemius muscle and in cardiac muscle of rats. Exp Physiol 91:983–994. doi:expphysiol.2006.033571
Meier H, Bullinger J, Marx G, Deten A, Horn LC, Rassler B, Zimmer HG, Briest W (2009) Crucial role of interleukin-6 in the development of norepinephrine-induced left ventricular remodeling in mice. Cell Physiol Biochem 23:327–334. doi:000218180
Muhlfeld C, Nyengaard JR, Mayhew TM (2010) A review of state-of-the-art stereology for better quantitative 3D morphology in cardiac research. Cardiovasc Pathol 19:65–82. doi:S1054-8807(08)00161-0
Niemann B, Chen Y, Issa H, Silber RE, Rohrbach S (2010) Caloric restriction delays cardiac ageing in rats: role of mitochondria. Cardiovasc Res 88:267–276. doi:cvq273
Palacios OM, Carmona JJ, Michan S, Chen KY, Manabe Y, Ward JL 3rd, Goodyear LJ, Tong Q (2009) Diet and exercise signals regulate SIRT3 and activate AMPK and PGC-1alpha in skeletal muscle. Aging (Albany NY) 1:771–783
Pillai JB, Isbatan A, Imai S, Gupta MP (2005) Poly(ADP-ribose) polymerase-1-dependent cardiac myocyte cell death during heart failure is mediated by NAD+ depletion and reduced Sir2alpha deacetylase activity. J Biol Chem 280:43121–43130. doi:M506162200
Pillai VB, Sundaresan NR, Kim G, Gupta M, Rajamohan SB, Pillai JB, Samant S, Ravindra PV, Isbatan A, Gupta MP (2010) Exogenous NAD blocks cardiac hypertrophic response via activation of the SIRT3-LKB1-AMP-activated kinase pathway. J Biol Chem 285:3133–3144. doi:M109.077271
Rimbaud S, Sanchez H, Garnier A, Fortin D, Bigard X, Veksler V, Ventura-Clapier R (2009) Stimulus specific changes of energy metabolism in hypertrophied heart. J Mol Cell Cardiol 46:952–959
Rodgers JT, Lerin C, Gerhart-Hines Z, Puigserver P (2008) Metabolic adaptations through the PGC-1 alpha and SIRT1 pathways. FEBS Lett 582:46–53. doi:S0014-5793(07)01178-7
Rodgers JT, Lerin C, Haas W, Gygi SP, Spiegelman BM, Puigserver P (2005) Nutrient control of glucose homeostasis through a complex of PGC-1alpha and SIRT1. Nature 434:113–118. doi:nature03354
Rohrbach S, Gruenler S, Teschner M, Holtz J (2006) The thioredoxin system in aging muscle: key role of mitochondrial thioredoxin reductase in the protective effects of caloric restriction? Am J Physiol Regul Integr Comp Physiol 291:R927–R935. doi:00890.2005
Salvi M, Morrice NA, Brunati AM, Toninello A (2007) Identification of the flavoprotein of succinate dehydrogenase and aconitase as in vitro mitochondrial substrates of Fgr tyrosine kinase. FEBS Lett 581:5579–5585. doi:S0014-5793(07)01135-0
Scheubel RJ, Tostlebe M, Simm A, Rohrbach S, Gellerich FN, Silber RE, Holtz J (2002) Dysfunction of mitochondrial respiratory chain complex I in human failing myocardium is not due to disturbed mitochondrial gene expression. J Am Coll Cardiol 40:2174–2181. doi:S0735109702026001
Schwarzer M, Britton SL, Koch LG, Wisloff U, Doenst T (2010) Low intrinsic aerobic exercise capacity and systemic insulin resistance are not associated with changes in myocardial substrate oxidation or insulin sensitivity. Basic Res Cardiol 105:357–364. doi:10.1007/s00395-010-0087-2
Shi T, Wang F, Stieren E, Tong Q (2005) SIRT3, a mitochondrial sirtuin deacetylase, regulates mitochondrial function and thermogenesis in brown adipocytes. J Biol Chem 280:13560–13567. doi:M414670200
Sundaresan NR, Gupta M, Kim G, Rajamohan SB, Isbatan A, Gupta MP (2009) Sirt3 blocks the cardiac hypertrophic response by augmenting Foxo3a-dependent antioxidant defense mechanisms in mice. J Clin Invest 119:2758–2771. doi:39162
Tomas E, Tsao TS, Saha AK, Murrey HE, Zhang Cc C, Itani SI, Lodish HF, Ruderman NB (2002) Enhanced muscle fat oxidation and glucose transport by ACRP30 globular domain: acetyl-CoA carboxylase inhibition and AMP-activated protein kinase activation. Proc Natl Acad Sci 99:16309–16313. doi:10.1073/pnas.222657499
Wallenius V, Wallenius K, Ahren B, Rudling M, Carlsten H, Dickson SL, Ohlsson C, Jansson JO (2002) Interleukin-6-deficient mice develop mature-onset obesity. Nat Med 8:75–79. doi:10.1038/nm0102-75