The effect of 12 weeks of aerobic exercise on mitochondrial dynamics in cardiac myocytes of type 2 diabetic rats

Original Article
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Abstract

Background

Mitochondrial dynamics disorders contribute to the pathogenesis of many diseases involving type 2 diabetes. It appears that exercise training is a strategy for reversing the unbalance between fusion and fission, but, to our understanding, effects of aerobic exercise on this particular issue have not been studied in cardiac myocytes.

Aims

To demonstrate if 12 weeks of aerobic exercise has a significant impact on Dynamin Related Protein 1 (DRP1), Mitofusin2 (MFN2) and Optic Atrophy 1 (OPA1) expressions in cardiac muscle of type 2 diabetic rats.

Methods

10 Wistar rats with an average age of 10 weeks were divided randomly into two groups of five: diabetic control and diabetic exercise. The latter was submitted to a 12-week (5 days a week, 30 min/day) aerobic exercise. 48 h after the last session of exercise, cardiac samples were obtained for genetic experiments. T-test was used for data analysis at p ≤ 0.05.

Results

OPA1 expression was increased significantly (p = 0.03) while MFN2 and DRP1 expressions were elevated insignificantly (p = 0.165, p = 0.19).

Conclusion

This study shows that aerobic training is likely to regulate mitochondrial fission and fusion in cardiac muscle of type 2 diabetic rats. Although more research is necessary.

Keywords

Mitochondrial dynamics Type 2 diabetes Aerobic exercise MFN2 OPA1 DRP1 

Notes

Compliance with ethical standards

Conflict of interest

The authors have no conflict of interest relevant to this article.

Ethical approval

All applicable international, national, and/or institutional guidelines for the care and use of animals were followed.

Informed consent

For this type of study, formal consent is not required.

References

  1. 1.
    Archer SL (2013) Mitochondrial dynamics–mitochondrial fission and fusion in human diseases. N Engl J Med 369:2236–2251.  https://doi.org/10.1056/NEJMra1215233 CrossRefPubMedGoogle Scholar
  2. 2.
    Sivitz WI, Yorek MA (2010) Mitochondrial dysfunction in diabetes: from molecular mechanisms to functional significance and therapeutic opportunities. Antioxid Redox Signal 12:537–577.  https://doi.org/10.1089/ars.2009.2531 CrossRefPubMedPubMedCentralGoogle Scholar
  3. 3.
    Ishihara N, Otera H, Oka T, Mihara K (2012) Regulation and physiologic functions of GTPases in mitochondrial fusion and fission in mammals. Antioxid Redox Signal 19:121001062245003.  https://doi.org/10.1089/ars.2012.4830 Google Scholar
  4. 4.
    Yoon Y, Krueger EW, Oswald BJ, McNiven MA (2003) The mitochondrial protein hFis1 regulates mitochondrial fission in mammalian cells through an interaction with the dynamin-like protein DLP1. Mol Cell Biol 23:5409–5420.  https://doi.org/10.1128/MCB.23.15.5409-5420.2003 CrossRefPubMedPubMedCentralGoogle Scholar
  5. 5.
    Cipolat S, Martins de Brito O, Dal Zilio B, Scorrano L (2004) OPA1 requires mitofusin 1 to promote mitochondrial fusion. Proc Natl Acad Sci USA 101:15927–15932.  https://doi.org/10.1073/pnas.0407043101 CrossRefPubMedPubMedCentralGoogle Scholar
  6. 6.
    Chen H, Detmer SA, Ewald AJ, Griffin EE, Fraser SE, Chan DC (2003) Mitofusins Mfn1 and Mfn2 coordinately regulate mitochondrial fusion and are essential for embryonic development. J Cell Biol 160:189–200.  https://doi.org/10.1083/jcb.200211046 CrossRefPubMedPubMedCentralGoogle Scholar
  7. 7.
    Santel A, Fuller MT (2001) Control of mitochondrial morphology by a human mitofusin. J Cell Sci 114:867–874PubMedGoogle Scholar
  8. 8.
    Youle RJ, van der Bliek AM (2012) Mitochondrial fission, fusion, and stress. Science 337:1062–1065.  https://doi.org/10.1126/science.1219855 CrossRefPubMedPubMedCentralGoogle Scholar
  9. 9.
    Bach D, Pich S, Soriano FX, Vega N, Baumgartner B, Oriola J, Daugaard JR, Lloberas J, Camps M, Zierath JR, Rabasa-Lhoret R, Wallberg-Henriksson H, Laville M, Palacín M, Vidal H, Rivera F, Brand M, Zorzano A (2003) Mitofusin-2 determines mitochondrial network architecture and mitochondrial metabolism: a novel regulatory mechanism altered in obesity. J Biol Chem 278:17190–17197.  https://doi.org/10.1074/jbc.M212754200 CrossRefPubMedGoogle Scholar
  10. 10.
    Bakeeva LE, Chentsov YS, Skulachev VP (1978) Mitochondrial framework (reticulum mitochondriale) in rat diaphragm muscle. BBA Bioenerg 501:349–369.  https://doi.org/10.1016/0005-2728(78)90104-4 CrossRefGoogle Scholar
  11. 11.
    Kirkwood SP, Munn EA, Brooks GA (1986) Mitochondrial reticulum in limb skeletal muscle. Am J Physiol 251:C395–402CrossRefPubMedGoogle Scholar
  12. 12.
    Wai T, Langer T (2016) Mitochondrial dynamics and metabolic regulation. Trends Endocrinol Metab 27:105–117.  https://doi.org/10.1016/j.tem.2015.12.001 CrossRefPubMedGoogle Scholar
  13. 13.
    Lee Y, Jeong S, Karbowski M, Smith C, Youle R (2004) Roles of the mammalian mitochondrial fission and fusion mediators Fis1, Drp1, and Opa1 in apoptosis. Mol Biol Cell 15:5001–5015CrossRefPubMedPubMedCentralGoogle Scholar
  14. 14.
    Ikeda Y, Sciarretta S, Nagarajan N, Rubattu S, Volpe M, Frati G, Sadoshima J (2014) New insights into the role of mitochondrial dynamics and autophagy during oxidative stress and aging in the heart. Oxid Med Cell Longev.  https://doi.org/10.1155/2014/210934 PubMedPubMedCentralGoogle Scholar
  15. 15.
    Kelley DE, He J, Menshikova EV, Ritov VB (2002) Dysfunction of mitochondria in human skeletal muscle in type 2 diabetes. Diabetes 51:2944–2950.  https://doi.org/10.2337/diabetes.51.10.2944 CrossRefPubMedGoogle Scholar
  16. 16.
    Mootha VK, Lindgren CM, Eriksson K-F, Subramanian A, Sihag S, Lehar J, Puigserver P, Carlsson E, Ridderstråle M, Laurila E, Houstis N, Daly MJ, Patterson N, Mesirov JP, Golub TR, Tamayo P, Spiegelman B, Lander ES, Hirschhorn JN, Altshuler D, Groop LC (2003) PGC-1α-responsive genes involved in oxidative phosphorylation are coordinately downregulated in human diabetes. Nat Genet 34:267–273.  https://doi.org/10.1038/ng1180 CrossRefPubMedGoogle Scholar
  17. 17.
    Patti ME, Butte AJ, Crunkhorn S, Cusi K, Berria R, Kashyap S, Miyazaki Y, Kohane I, Costello M, Saccone R, Landaker EJ, Goldfine AB, Mun E, DeFronzo R, Finlayson J, Kahn CR, Mandarino LJ (2003) Coordinated reduction of genes of oxidative metabolism in humans with insulin resistance and diabetes: potential role of PGC1 and NRF1. Proc Natl Acad Sci USA 100:8466–8471.  https://doi.org/10.1073/pnas.1032913100 CrossRefPubMedPubMedCentralGoogle Scholar
  18. 18.
    Bach D, Naon D, Pich S, Soriano FX, Vega N, Rieusset J, Laville M, Guillet C, Boirie Y, Wallberg-Henriksson H, Manco M, Calvani M, Castagneto M, Palacín M, Mingrone G, Zierath JR, Vidal H, Zorzano A (2005) Expression of Mfn2, the charcot-marie-tooth neuropathy type 2A gene, in human skeletal muscle. Diabetes 54:2685–2693.  https://doi.org/10.2337/diabetes.54.9.2685 CrossRefPubMedGoogle Scholar
  19. 19.
    Zorzano A, Hernández-Alvarez MI, Palacín M, Mingrone G (2010) 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 Bioenerg 1797:1028–1033.  https://doi.org/10.1016/j.bbabio.2010.02.017 CrossRefGoogle Scholar
  20. 20.
    Sebastián D, Hernández-Alvarez MI, Segalés J, Sorianello E, Muñoz JP, Sala D, Waget A, Liesa M, Paz JC, Gopalacharyulu P, Orešič M, Pich S, Burcelin R, Palacín M, Zorzano A (2012) Mitofusin 2 (Mfn2) links mitochondrial and endoplasmic reticulum function with insulin signaling and is essential for normal glucose homeostasis. Proc Natl Acad Sci USA 109:5523–5528.  https://doi.org/10.1073/pnas.1108220109 CrossRefPubMedPubMedCentralGoogle Scholar
  21. 21.
    Nochez Y, Arsene S, Gueguen N, Chevrollier A, Ferré M, Guillet V, Desquiret V, Toutain A, Bonneau D, Procaccio V, Amati-Bonneau P, Pisella P-J, Reynier P (2009) Acute and late-onset optic atrophy due to a novel OPA1 mutation leading to a mitochondrial coupling defect. Mol Vis 15:598–608PubMedPubMedCentralGoogle Scholar
  22. 22.
    Evans JL, Goldfine ID, Maddux BA, Grodsky GM (2003) Are oxidative stress-activated signaling pathways mediators of insulin resistance and β-cell dysfunction? Diabetes 52:1–8.  https://doi.org/10.2337/diabetes.52.1.1 CrossRefPubMedGoogle Scholar
  23. 23.
    Favier FB, Britto FA, Poncon B, Begue G, Chabi B, Reboul C, Meyer G, Py G (2015) Endurance training prevents negative effects of the hypoxia mimetic dimethyloxalylglycine on cardiac and skeletal muscle function. J Appl Physiol.  https://doi.org/10.1152/japplphysiol.00171.2015 PubMedGoogle Scholar
  24. 24.
    Perry CGR, Lally J, Holloway GP, Heigenhauser GJF, Bonen A, Spriet LL (2010) Repeated transient mRNA bursts precede increases in transcriptional and mitochondrial proteins during training in human skeletal muscle. J Physiol 588:4795–4810.  https://doi.org/10.1113/jphysiol.2010.199448 CrossRefPubMedPubMedCentralGoogle Scholar
  25. 25.
    Bo H, Zhang Y, Ji LL (2010) Redefining the role of mitochondria in exercise: a dynamic remodeling. Ann N Y Acad Sci 1201:121–128.  https://doi.org/10.1111/j.1749-6632.2010.05618.x CrossRefPubMedGoogle Scholar
  26. 26.
    Ding H, Jiang N, Liu H, Liu X, Liu D, Zhao F, Wen L, Liu S, Ji LL, Zhang Y (2010) Response of mitochondrial fusion and fission protein gene expression to exercise in rat skeletal muscle. Biochim Biophys Acta Gen Subj 1800:250–256.  https://doi.org/10.1016/j.bbagen.2009.08.007 CrossRefGoogle Scholar
  27. 27.
    Jiang HK, Wang YH, Sun L, He X, Zhao M, Feng ZH, Yu XJ, Zang WJ (2014) Aerobic interval training attenuates mitochondrial dysfunction in rats post-myocardial infarction: roles of mitochondrial network dynamics. Int J Mol Sci 15:5304–5322.  https://doi.org/10.3390/ijms15045304 CrossRefPubMedPubMedCentralGoogle Scholar
  28. 28.
    Szkudelski T (2012) Streptozotocin-nicotinamide-induced diabetes in the rat. Characteristics of the experimental model. Exp Biol Med (Maywood) 237(5):481–490.  https://doi.org/10.1258/ebm.2012.011372 CrossRefGoogle Scholar
  29. 29.
    Pierre W, Gildas AJH, Ulrich MC, Modeste W-N, Benoît NT, Albert K (2012) Hypoglycemic and hypolipidemic effects of Bersama engleriana leaves in nicotinamide/streptozotocin-induced type 2 diabetic rats. BMC Complement Altern Med 12:264.  https://doi.org/10.1186/1472-6882-12-264 CrossRefPubMedPubMedCentralGoogle Scholar
  30. 30.
    Mogharnasi M, Gaeini A, Sheikholeslami Vatani D, Rahnama N, Arjmandi B, Bambaeichi E (2011) Effect of acute and prolonged periods of aerobic training and detraining on novel inflammatory marker: the predictive of cardiovascular disease in Wistar rats. Gazz Medica Ital Arch Per Le Sci Mediche 170:307–313Google Scholar
  31. 31.
    Lawler JM, Powers SK, Hammeren J, Martin AD (1993) Oxygen cost of treadmill running in 24-month-old Fischer-344 rats. Med Sci Sports Exerc 25:1259–1264.  https://doi.org/10.1249/00005768-199311000-00009 CrossRefPubMedGoogle Scholar
  32. 32.
    Taji Tabas A, Mogharnasi M (2015) The effect of 10 week resistance exercise training on serum levels of nesfatin-1 and insulin resistance index in woman with type 2 diabetes. Iran J Diabetes Metab 14:179–188Google Scholar
  33. 33.
    Cheng K-CC, Asakawa A, Li Y-XX, Chung H-HH, Amitani H, Ueki T, Cheng J-TT, Inui A (2014) Silymarin induces insulin resistance through an increase of phosphatase and tensin homolog in wistar rats. PLoS ONE 9:e84550.  https://doi.org/10.1371/journal.pone.0084550 CrossRefPubMedPubMedCentralGoogle Scholar
  34. 34.
    Katz A, Nambi SS, Mather K, Baron AD, Follmann DA, Sullivan G, Quon MJ (2000) Quantitative insulin sensitivity check index: a simple, accurate method for assessing insulin sensitivity in humans. J Clin Endocrinol Metab 85:2402–2410.  https://doi.org/10.1210/jc.85.7.2402 CrossRefPubMedGoogle Scholar
  35. 35.
    Gaeini AA, Bahramian A, Javidi M (2013) The effect of eight weeks of resistance training on stimulatory and inhibitory factors of cardiac microvascular injuries in Wistar diabetic rats. JME 3:21–32Google Scholar
  36. 36.
    Jorge L, Paulini J, Silva C, Rampaso R, Luiz R, Lima W, Scavasin G, Schor N (2013) Exercise training improves cardiac mitofusin 2 expression in diabetes. Hypertension 62:613Google Scholar
  37. 37.
    Fealy CE, Mulya A, Lai N, Kirwan JP (2014) Exercise training decreases activation of the mitochondrial fission protein dynamin-related protein-1 in insulin resistant human skeletal muscle. J Appl Physiol.  https://doi.org/10.1152/japplphysiol.01064.2013 PubMedPubMedCentralGoogle Scholar
  38. 38.
    Walder K, Kerr-Bayles L, Civitarese A, Jowett J, Curran J, Elliott K, Trevaskis J, Bishara N, Zimmet P, Mandarino L, Ravussin E, Blangero J, Kissebah A, Collier GR (2005) The mitochondrial rhomboid protease PSARL is a new candidate gene for type 2 diabetes. Diabetologia 48:459–468.  https://doi.org/10.1007/s00125-005-1675-9 CrossRefPubMedGoogle Scholar
  39. 39.
    Hernandez-Alvarez MI, Thabit H, Burns N, Shah S, Brema I, Hatunic M, Finucane F, Liesa M, Chiellini C, Naon D, Zorzano A, Nolan JJ (2010) Subjects with early-onset type 2 diabetes show defective activation of the skeletal muscle PGC-1α/mitofusin-2 regulatory pathway in response to physical activity. Diabetes Care 33:645–651.  https://doi.org/10.2337/dc09-1305 CrossRefPubMedGoogle Scholar
  40. 40.
    Holloszy JO, Coyle EF (1984) Adaptations of skeletal muscle to endurance exercise and their metabolic consequences. J Appl Physiol 56:831–838CrossRefPubMedGoogle Scholar
  41. 41.
    Cartoni R, Leger B, Hock MB, Praz M, Crettenand A, Pich S, Ziltener JL, Luthi F, Deriaz O, Zorzano A, Gobelet C, Kralli A, Russell AP (2005) Mitofusins 1/2 and ERRα expression are increased in human skeletal muscle after physical exercise. J Physiol 567:349–358.  https://doi.org/10.1113/jphysiol.2005.092031 CrossRefPubMedPubMedCentralGoogle Scholar
  42. 42.
    Joseph A-M, Joanisse DR, Baillot RG, Hood DA (2012) mitochondrial dysregulation in the pathogenesis of diabetes: potential for mitochondrial biogenesis-mediated interventions. Exp Diabetes Res.  https://doi.org/10.1155/2012/642038 PubMedGoogle Scholar
  43. 43.
    Shen T, Zheng M, Cao C, Chen C, Tang J, Zhang W, Cheng H, Chen KH, Xiao RP (2007) Mitofusin-2 is a major determinant of oxidative stress-mediated heart muscle cell apoptosis. J Biol Chem 282:23354–23361.  https://doi.org/10.1074/jbc.M702657200 CrossRefPubMedGoogle Scholar
  44. 44.
    Ikeda Y, Sciarretta S, Nagarajan N, Rubattu S, Volpe M, Frati G, Sadoshima J (2014) New insights into the role of mitochondrial dynamics and autophagy during oxidative stress and aging in the heart. Oxid Med Cell Longev.  https://doi.org/10.1155/2014/210934 PubMedPubMedCentralGoogle Scholar
  45. 45.
    Ziolkowski W, Flis DJ, Halon M, Vadhana DMS, Olek RA, Carloni M, Antosiewicz J, Kaczor JJ, Gabbianelli R (2015) Prolonged swimming promotes cellular oxidative stress and p66Shc phosphorylation, but does not induce oxidative stress in mitochondria in the rat heart. Free Radic Res 49:7–16.  https://doi.org/10.3109/10715762.2014.968147 CrossRefPubMedGoogle Scholar
  46. 46.
    Benedini S, Caimi A, Alberti G, Terruzzi I, Dellerma N, La Torre A, Luzi L (2010) Increase in homocysteine levels after a half-marathon running: a detrimental metabolic effect of sport? Sport Sci Health 6:35–42.  https://doi.org/10.1007/s11332-010-0094-6 CrossRefGoogle Scholar
  47. 47.
    Wang K, Klionsky DJ (2011) Mitochondria removal by autophagy. Autophagy 7:297–300.  https://doi.org/10.4161/auto.7.3.14502 CrossRefPubMedPubMedCentralGoogle Scholar
  48. 48.
    Sciarretta S, Zhai P, Volpe M, Sadoshima J (2012) Pharmacological modulation of autophagy during cardiac stress. J Cardiovasc Pharmacol 60:235–241.  https://doi.org/10.1097/FJC.0b013e3182575f61 CrossRefPubMedPubMedCentralGoogle Scholar
  49. 49.
    Melov S, Hinerfeld D, Esposito L, Wallace DC (1997) Multi-organ characterization of mitochondrial genomic rearrangements in ad libitum and caloric restricted mice show striking somatic mitochondrial DNA rearrangements with age. Nucleic Acids Res 25:974–982.  https://doi.org/10.1093/nar/25.5.974 CrossRefPubMedPubMedCentralGoogle Scholar
  50. 50.
    Yan Z, Lira VA, Greene NP (2012) Exercise training-induced regulation of mitochondrial quality. Exerc Sport Sci Rev 40:159–164.  https://doi.org/10.1097/JES.0b013e3182575599 PubMedPubMedCentralGoogle Scholar
  51. 51.
    Finkel T, Holbrook NJ, Alberti A, Bolognini L, Macciantelli D, Caratelli M, Aviram M, Bełtowski J, Wójcicka G, Marciniak A, Capeillère-Blandin C, Gausson V, Descamps-Latscha B, Witko-Sarsat V, Chen S, Nilsen J, Brinton RD, Droge W, Erel O, Finkel T, Holbrook NJ, Jacobs AH, Winkler A, Castro MG, Lowenstein P, Johnson GL, Lapadat R, Khersonsky O, Tawfik DS, Gu X, Huang Y, Levison BS, Gerstenecker G, DiDonato AJ, Hazen LB, Lee J, Gogonea V, DiDonato JA, Hazen SL, Wu Z, Riwanto M, Gao S, Levison BS, Gu X, Fu X, Wagner MA, Besler C, Gerstenecker G, Zhang R, Li X, DiDonato AJ, Gogonea V, Tang WHW, Smith JD, Plow EF, Fox PL, Shih DM, Lusis AJ, Fisher EA, DiDonato JA, Landmesser U, Hazen SL, Matsuoka Y, Picciano M, La Francois J, Duff K, Mtsuokaa Y, Picciano M, La Francois J, Duff K, Mills E, Dong X, Fudi W, Xu H, Praticò D, Rosenblat M, Gaidukov L, Khersonsky O, Vaya J, Oren R, Tawfik DS, Aviram M, Yin F, Yao J, Sancheti H, Feng T, Melcangi RC, Morgan TE, Finch CE, Pike CJ, Mack WJ, Cadenas E, Brinton RD, McGrath LT, McGleenon BM, Brennan S, McColl D, McILroy S, Passmore AP, Wildsmith KR, Holley M, Savage JC, Skerrett R, Landreth GE, Hayashi H, Gupta A, Iadecola C, Vitali C, Wellington CL, Calabresi L, Cervellati C, Bergamini CM, Mckhann GM, Knopman DS, Chertkow H, Hyman BT, Jack CR, Kawas CH, Klunk WE, Koroshetz WJ, Manly JJ, Mayeux R, Mohs RC, Morris JC, Rossor MN, Scheltens P, Carillo MC, Thies B, Weintraub S, Phelps CH, Gu X, Huang Y, Levison BS, Gerstenecker G, DiDonato AJ, Hazen LB, Lee J, Gogonea V, DiDonato JA, Hazen SL, Klosinski LP, Yao J, Yin F, Fonteh AN, Harrington MG, Christensen TA, Trushina E, Diaz R, Qm C, Simulations MM, Oxon MC, Furlong CE, Richter RJ, Seidel SL, Motulsky AG, Wojtunik-kulesza KA, Oniszczuk A, Oniszczuk T, Waksmundzka-hajnos M (2000) Oxidants, oxidative stress and the biology of ageing. Nature 408:239–247.  https://doi.org/10.1038/35041687 CrossRefPubMedGoogle Scholar
  52. 52.
    Parone PA, Da Druz S, Tondera D, Mattenberger Y, James DI, Maechler P, Barja F, Martinou JC (2008) Preventing mitochondrial fission impairs mitochondrial function and leads to loss of mitochondrial DNA. PLoS ONE.  https://doi.org/10.1371/journal.pone.0003257 PubMedPubMedCentralGoogle Scholar

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© Springer-Verlag Italia S.r.l., part of Springer Nature 2018

Authors and Affiliations

  1. 1.Faculty of Physical Education and Sports SciencesUniversity of TehranTehranIran
  2. 2.TehranIran

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