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Basic Research in Cardiology

, Volume 106, Issue 6, pp 1221–1234 | Cite as

Mitochondrial biogenesis and PGC-1α deacetylation by chronic treadmill exercise: differential response in cardiac and skeletal muscle

  • Ling Li
  • Christian Mühlfeld
  • Bernd Niemann
  • Ruping Pan
  • Rong Li
  • Denise Hilfiker-Kleiner
  • Ying Chen
  • Susanne RohrbachEmail author
Original Contribution

Abstract

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.

Keywords

Exercise Hypertrophy Mitochondrial biogenesis Heart 

Notes

Acknowledgments

We appreciate the technical assistance of R. Gall, B. Heinze and N. Woitasky. We would also like to thank Gerhard Kripp for his expert technical assistance in the electron microscopic work. This study was supported by the DFG (RO 2328/2-1) and Deutsche Stiftung für Herzforschung (F/05/05).

Supplementary material

395_2011_213_MOESM1_ESM.pdf (4.1 mb)
Supplementary material 1 (PDF 4,165 kb)

References

  1. 1.
    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 PubMedCrossRefGoogle Scholar
  2. 2.
    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 PubMedCrossRefGoogle Scholar
  3. 3.
    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 PubMedCrossRefGoogle Scholar
  4. 4.
    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 PubMedCrossRefGoogle Scholar
  5. 5.
    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[ PubMedCrossRefGoogle Scholar
  6. 6.
    Boengler K, Schulz R, Heusch G (2009) Loss of cardioprotection with ageing. Cardiovasc Res 83:247–261. doi: cvp033 PubMedCrossRefGoogle Scholar
  7. 7.
    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 PubMedCrossRefGoogle Scholar
  8. 8.
    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 PubMedCrossRefGoogle Scholar
  9. 9.
    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 PubMedCrossRefGoogle Scholar
  10. 10.
    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 PubMedCrossRefGoogle Scholar
  11. 11.
    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 PubMedCrossRefGoogle Scholar
  12. 12.
    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 PubMedCrossRefGoogle Scholar
  13. 13.
    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 PubMedCrossRefGoogle Scholar
  14. 14.
    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 PubMedCrossRefGoogle Scholar
  15. 15.
    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 PubMedCrossRefGoogle Scholar
  16. 16.
    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 PubMedGoogle Scholar
  17. 17.
    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 PubMedCrossRefGoogle Scholar
  18. 18.
    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 PubMedCrossRefGoogle Scholar
  19. 19.
    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 PubMedCrossRefGoogle Scholar
  20. 20.
    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 PubMedCrossRefGoogle Scholar
  21. 21.
    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 PubMedCrossRefGoogle Scholar
  22. 22.
    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 PubMedCrossRefGoogle Scholar
  23. 23.
    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 CrossRefGoogle Scholar
  24. 24.
    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 PubMedCrossRefGoogle Scholar
  25. 25.
    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 PubMedCrossRefGoogle Scholar
  26. 26.
    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 PubMedCrossRefGoogle Scholar
  27. 27.
    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 PubMedCrossRefGoogle Scholar
  28. 28.
    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 52:164–168PubMedGoogle Scholar
  29. 29.
    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 PubMedCrossRefGoogle Scholar
  30. 30.
    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 PubMedCrossRefGoogle Scholar
  31. 31.
    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 PubMedCrossRefGoogle Scholar
  32. 32.
    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 PubMedCrossRefGoogle Scholar
  33. 33.
    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 PubMedCrossRefGoogle Scholar
  34. 34.
    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 PubMedCrossRefGoogle Scholar
  35. 35.
    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 PubMedCrossRefGoogle Scholar
  36. 36.
    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 PubMedCrossRefGoogle Scholar
  37. 37.
    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 PubMedCrossRefGoogle Scholar
  38. 38.
    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 PubMedCrossRefGoogle Scholar
  39. 39.
    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 PubMedCrossRefGoogle Scholar
  40. 40.
    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 PubMedCrossRefGoogle Scholar
  41. 41.
    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 PubMedCrossRefGoogle Scholar
  42. 42.
    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) 1:771–783Google Scholar
  43. 43.
    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 PubMedCrossRefGoogle Scholar
  44. 44.
    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 PubMedCrossRefGoogle Scholar
  45. 45.
    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 46:952–959PubMedCrossRefGoogle Scholar
  46. 46.
    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 PubMedCrossRefGoogle Scholar
  47. 47.
    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 PubMedCrossRefGoogle Scholar
  48. 48.
    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 PubMedCrossRefGoogle Scholar
  49. 49.
    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 PubMedCrossRefGoogle Scholar
  50. 50.
    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 PubMedCrossRefGoogle Scholar
  51. 51.
    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 PubMedCrossRefGoogle Scholar
  52. 52.
    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 PubMedCrossRefGoogle Scholar
  53. 53.
    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 PubMedGoogle Scholar
  54. 54.
    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 PubMedCrossRefGoogle Scholar
  55. 55.
    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 PubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag 2011

Authors and Affiliations

  • Ling Li
    • 1
  • Christian Mühlfeld
    • 2
  • Bernd Niemann
    • 3
  • Ruping Pan
    • 1
  • Rong Li
    • 4
  • Denise Hilfiker-Kleiner
    • 5
  • Ying Chen
    • 4
  • Susanne Rohrbach
    • 1
    • 4
    Email author
  1. 1.Institute of PhysiologyJustus Liebig University GiessenGiessenGermany
  2. 2.Institute of Anatomy and Cell BiologyJustus Liebig University GiessenGiessenGermany
  3. 3.Department of Cardiac and Vascular SurgeryJustus Liebig University GiessenGiessenGermany
  4. 4.Institute of PathophysiologyMartin Luther University Halle-WittenbergHalleGermany
  5. 5.Department of Cardiology and AngiologyMedical School HannoverHannoverGermany

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