Cardiovascular Toxicology

, Volume 19, Issue 5, pp 422–431 | Cite as

High Intensity Interval Training Ameliorates Mitochondrial Dysfunction in the Left Ventricle of Mice with Type 2 Diabetes

  • Fredrik H. BækkerudEmail author
  • Simona Salerno
  • Paola Ceriotti
  • Cecilie Morland
  • Jon Storm-Mathisen
  • Linda H. Bergersen
  • Morten A. Høydal
  • Daniele Catalucci
  • Tomas O. Stølen


Both human and animal studies have shown mitochondrial and contractile dysfunction in hearts of type 2 diabetes mellitus (T2DM). Exercise training has shown positive effects on cardiac function, but its effect on the mitochondria have been insufficiently explored. The aim of this study was to assess the effect of exercise training on mitochondrial function in T2DM hearts. We divided T2DM mice (db/db) into a sedentary and an interval training group at 8 weeks of age and used heterozygote db/+ as controls. After 8 weeks of training, we evaluated mitochondrial structure and function, as well as the levels of mRNA and proteins involved in key metabolic processes from the left ventricle. db/db animals showed decreased oxidative phosphorylation capacity and fragmented mitochondria. Mitochondrial respiration showed a blunted response to Ca2+ along with reduced protein levels of the mitochondrial calcium uniporter. Exercise training ameliorated the reduced oxidative phosphorylation in complex (C) I + II, CII and CIV, but not CI or Ca2+ response. Mitochondrial fragmentation was partially restored. mRNA levels of isocitrate, succinate and oxoglutarate dehydrogenase were increased in db/db mice and normalized by exercise training. Exercise training induced an upregulation of two transcripts of peroxisome proliferator activated receptor gamma coactivator 1 alpha (PGC1α1 and PGC1α4) previously linked to endurance training adaptations and strength training adaptations, respectively. The T2DM heart showed mitochondrial dysfunction at multiple levels and exercise training ameliorated some, but not all mitochondrial dysfunctions.


Mitochondria Exercise training Diabetes Diabetic cardiomyopathy 



Late LV filling


Mitochondrial electron transport chain complex (ex. CII = complex II)


Early LV filling


Myocardial velocity


Ejection fraction


Electron transport chain


High intensity interval training


Isocitrate dehydrogenase


Left ventricle


Mitochondrial calcium uniporter


Oxoglutarate dehydrogenase


Oxidative phosphorylation


Peroxisome proliferator-activated receptor gamma coactivator 1-alpha


Peroxisome proliferator-activated receptorγ


Succinate dehydrogenase


Type 2 diabetes mellitus


Mitochondrial transcription factor A


Author Contributions

FHB, DC and TOS designed the study, FHB, SS, PC and TOS contributed to data collection. FHB, SS, PC, CM, JS, LHB, MAH, DC, TOS contributed to interpretation of the data and drafting and revising the manuscript.


This work was supported by grants from The Research Council of Norway (FRIPRO Project Number 214458) and (Young Outstanding Investigators Project Number 231764), The Liaison Committee between the Central Norway Regional Health Authority (Project Number 90158300) and UNIKARD (Project Number 217777/H10).

Compliance with Ethical Standards

Conflict of interest

The authors declare that they have no competing interests.

Ethical Approval

The study was approved by the Norwegian council for animal research.

Supplementary material

12012_2019_9514_MOESM1_ESM.tif (383 kb)
Supplementary Figure 1—Db/db mice develop T2DM. (a) Serum glucose and (b) triglycerides measured at 16 weeks of age. (c) Body weight measured at 8 and 16 weeks of age. *, significantly different (p<0.05) from pre value of the same group; ‡, significantly different (p<0.001) from db/db sed at the same time point; †, significantly different (p<0.001) from db/+ at the same time point. g, grams; ex, exercise trained group; sed, sedentary group. (TIF 382 KB)
12012_2019_9514_MOESM2_ESM.tif (420 kb)
Supplementary Figure 2—Exercise training ameliorates the decreased fitness in db/db mice. Maximal oxygen uptake (VO2max) at 8 and 16 weeks expressed both as (a) VO2max, ml·kg-1·min-1 and (b) VO2max, ml·kg-0.75·min-1. *, significantly different (p<0.05) from pre value of the same group; ‡, significantly different (p<0.001) from db/db sed at the same time point; †, significantly different (p<0.001) from db/+ at the same time point. g, grams; ex, exercise trained group; sed, sedentary group. (TIF 420 KB)
12012_2019_9514_MOESM3_ESM.png (65 kb)
Supplementary Figure 3—Example trace of the respiration protocol. Blue line = oxygen concentration, red line = oxygen consumption per mass. (PNG 64 KB)
12012_2019_9514_MOESM4_ESM.png (2.1 mb)
Supplementary Figure 4—Example trace of EM image analysis. White arrows point towards mitochondria, black arrows point towards areas that were excluded from the analysis (blood vessels). (PNG 2181 KB)
12012_2019_9514_MOESM5_ESM.docx (13 kb)
Supplementary Table 1 (DOCX 13 KB)


  1. 1.
    Collaborators GBDCoD. (2017). Global, regional, and national age-sex specific mortality for 264 causes of death, 1980–2016: A systematic analysis for the Global Burden of Disease Study 2016. Lancet, 390(10100), 1151–1210.CrossRefGoogle Scholar
  2. 2.
    Emerging Risk Factors Collaboration. (2010). Diabetes mellitus, fasting blood glucose concentration, and risk of vascular disease: A collaborative meta-analysis of 102 prospective studies. The Lancet, 375(9733), 2215–2222.CrossRefGoogle Scholar
  3. 3.
    Haffner, S. M., Lehto, S., Rönnemaa, T., Pyörälä, K., & Laakso, M. (1998). Mortality from coronary heart disease in subjects with type 2 diabetes and in nondiabetic subjects with and without prior myocardial infarction. New England Journal of Medicine, 339(4), 229–234.CrossRefPubMedGoogle Scholar
  4. 4.
    Donahoe, S. M., Stewart, G. C., McCabe, C. H., Mohanavelu, S., Murphy, S. A., Cannon, C. P., et al. (2007). Diabetes and mortality following acute coronary syndromes. JAMA, 298(7), 765–775.CrossRefPubMedGoogle Scholar
  5. 5.
    Jaffe, A. S., Spadaro, J. J., Schechtman, K., Roberts, R., Geltman, E. M., & Sobel, B. E. (1984). Increased congestive heart failure after myocardial infarction of modest extent in patients with diabetes mellitus. American Heart Journal, 108(1), 31–37.CrossRefPubMedGoogle Scholar
  6. 6.
    Belke, D. D., Larsen, T. S., Gibbs, E. M., & Severson, D. L. (2000). Altered metabolism causes cardiac dysfunction in perfused hearts from diabetic (db/db) mice. American Journal of Physiology Endocrinology and Metabolism, 279(5), E1104–E1113.CrossRefPubMedGoogle Scholar
  7. 7.
    Dabkowski, E. R., Baseler, W. A., Williamson, C. L., Powell, M., Razunguzwa, T. T., Frisbee, J. C., et al. (2010). Mitochondrial dysfunction in the type 2 diabetic heart is associated with alterations in spatially distinct mitochondrial proteomes. American Journal of Physiology-Heart and Circulatory Physiology, 299(2), H529–H540.CrossRefPubMedPubMedCentralGoogle Scholar
  8. 8.
    Boudina, S., Sena, S., Theobald, H., Sheng, X., Wright, J. J., Hu, X. X., et al. (2007). Mitochondrial energetics in the heart in obesity-related diabetes: Direct evidence for increased uncoupled respiration and activation of uncoupling proteins. Diabetes, 56(10), 2457–2466.CrossRefPubMedGoogle Scholar
  9. 9.
    Glancy, B., Willis, W. T., Chess, D. J., & Balaban, R. S. (2013). Effect of calcium on the oxidative phosphorylation cascade in skeletal muscle mitochondria. Biochemistry, 52(16), 2793–2809.CrossRefPubMedPubMedCentralGoogle Scholar
  10. 10.
    Denton, R. M. (2009). Regulation of mitochondrial dehydrogenases by calcium ions. Biochimica et Biophysica Acta (BBA)Bioenergetics, 1787(11), 1309–1316.CrossRefGoogle Scholar
  11. 11.
    Kwong, J. Q., Lu, X., Correll, R. N., Schwanekamp, J. A., Vagnozzi, R. J., Sargent, M. A., et al. (2015). The Mitochondrial calcium uniporter selectively matches metabolic output to acute contractile stress in the heart. Cell Reports, 12(1), 15–22.CrossRefPubMedPubMedCentralGoogle Scholar
  12. 12.
    Rasmussen, T. P., Wu, Y., Joiner, M. L., Koval, O. M., Wilson, N. R., Luczak, E. D., et al. (2015). Inhibition of MCU forces extramitochondrial adaptations governing physiological and pathological stress responses in heart. Proceedings of the National Academy of Sciences of the United States of America, 112(29), 9129–9134.CrossRefPubMedPubMedCentralGoogle Scholar
  13. 13.
    Diaz-Juarez, J., Suarez, J., Cividini, F., Scott, B. T., Diemer, T., Dai, A., et al. (2016). Expression of the mitochondrial calcium uniporter in cardiac myocytes improves impaired mitochondrial calcium handling and metabolism in simulated hyperglycemia. American Journal of Physiology Cell Physiology, 311(6), C1005–C10c13.CrossRefPubMedPubMedCentralGoogle Scholar
  14. 14.
    Suarez, J., Cividini, F., Scott, B. T., Lehmann, K., Diaz-Juarez, J., Diemer, T., et al. (2018). Restoring mitochondrial calcium uniporter expression in diabetic mouse heart improves mitochondrial calcium handling and cardiac function. Journal of Biological Chemistry, 293(21), 8182–8195.CrossRefPubMedGoogle Scholar
  15. 15.
    Myers, J., Prakash, M., Froelicher, V., Do, D., Partington, S., & Atwood, J. E. (2002). Exercise capacity and mortality among men referred for exercise testing. The New England Journal of Medicine, 346(11), 793–801.CrossRefPubMedGoogle Scholar
  16. 16.
    Wisloff, U., Nilsen, T. I., Droyvold, W. B., Morkved, S., Slordahl, S. A., & Vatten, L. J. (2006) A single weekly bout of exercise may reduce cardiovascular mortality: how little pain for cardiac gain? ‘The HUNT study, Norway’. European Journal of Cardiovascular Prevention and Rehabilitation: Official Journal of the European Society of Cardiology, Working Groups on Epidemiology & Prevention and Cardiac Rehabilitation and Exercise Physiology, 13(5):798–804.CrossRefGoogle Scholar
  17. 17.
    Manson, J. E., Greenland, P., LaCroix, A. Z., Stefanick, M. L., Mouton, C. P., Oberman, A., et al. (2002). Walking compared with vigorous exercise for the prevention of cardiovascular events in women. The New England Journal of Medicine, 347(10), 716–725.CrossRefPubMedGoogle Scholar
  18. 18.
    Swank, A. M., Horton, J., Fleg, J. L., Fonarow, G. C., Keteyian, S., Goldberg, L., et al. (2012). Modest increase in peak VO2 is related to better clinical outcomes in chronic heart failure patients: Results from heart failure and a controlled trial to investigate outcomes of exercise training. Circulation Heart Failure, 5(5), 579–585.CrossRefPubMedPubMedCentralGoogle Scholar
  19. 19.
    Tjonna, A. E., Lee, S. J., Rognmo, O., Stolen, T. O., Bye, A., Haram, P. M., et al. (2008). Aerobic interval training versus continuous moderate exercise as a treatment for the metabolic syndrome: A pilot study. Circulation, 118(4), 346–354.CrossRefPubMedPubMedCentralGoogle Scholar
  20. 20.
    Wisloff, U., Stoylen, A., Loennechen, J. P., Bruvold, M., Rognmo, O., Haram, P. M., et al. (2007). Superior cardiovascular effect of aerobic interval training versus moderate continuous training in heart failure patients: A randomized study. Circulation, 115(24), 3086–3094.CrossRefPubMedGoogle Scholar
  21. 21.
    Hollekim-Strand, S. M., Bjorgaas, M. R., Albrektsen, G., Tjonna, A. E., Wisloff, U., & Ingul, C. B. (2014). High-intensity interval exercise effectively improves cardiac function in patients with type 2 diabetes mellitus and diastolic dysfunction: A randomized controlled trial. Journal of the American College of Cardiology, 64(16), 1758–1760.CrossRefPubMedGoogle Scholar
  22. 22.
    Stølen, T. O., Høydal, M. A., Kemi, O. J., Catalucci, D., Ceci, M., Aasum, E., et al. (2009). Interval training normalizes cardiomyocyte function, diastolic Ca2+ control, and SR Ca2+ release Synchronicity in a Mouse Model of Diabetic cardiomyopathy. Circulation Research, 105(6), 527–536.CrossRefPubMedGoogle Scholar
  23. 23.
    Shao, C. H., Wehrens, X. H., Wyatt, T. A., Parbhu, S., Rozanski, G. J., Patel, K. P., et al. (2009). Exercise training during diabetes attenuates cardiac ryanodine receptor dysregulation. Journal of Applied Physiology, 106(4), 1280–1292.CrossRefPubMedPubMedCentralGoogle Scholar
  24. 24.
    Wang, H., Bei, Y., Lu, Y., Sun, W., Liu, Q., Wang, Y., et al. (2015). Exercise prevents cardiac injury and improves mitochondrial biogenesis in advanced diabetic cardiomyopathy with PGC-1alpha and Akt activation. Cellular Physiology and Biochemistry, 35(6), 2159–2168.CrossRefPubMedGoogle Scholar
  25. 25.
    Coleman, D. L., & Hummel, K. P. (1967). Studies with the mutation, diabetes, in the mouse. Diabetologia, 3(2), 238–248.CrossRefPubMedGoogle Scholar
  26. 26.
    Kemi, O. J., Loennechen, J. P., Wisløff, U., & Ellingsen, Ø (2002). Intensity-controlled treadmill running in mice: Cardiac and skeletal muscle hypertrophy. Journal of Applied Physiology, 93(4), 1301–1309.CrossRefPubMedGoogle Scholar
  27. 27.
    Ruas, J. L., White, J. P., Rao, R. R., Kleiner, S., Brannan, K. T., Harrison, B. C., et al. (2012). A PGC-1alpha isoform induced by resistance training regulates skeletal muscle hypertrophy. Cell, 151(6), 1319–1331.CrossRefPubMedPubMedCentralGoogle Scholar
  28. 28.
    Veeranki, S., Givvimani, S., Kundu, S., Metreveli, N., Pushpakumar, S., & Tyagi, S. C. (2016). Moderate intensity exercise prevents diabetic cardiomyopathy associated contractile dysfunction through restoration of mitochondrial function and connexin 43 levels in db/db mice. Journal of Molecular and Cellular Cardiology, 92, 163–173.CrossRefPubMedPubMedCentralGoogle Scholar
  29. 29.
    Hinkle, P. C., Kumar, M. A., Resetar, A., & Harris, D. L. (1991). Mechanistic stoichiometry of mitochondrial oxidative phosphorylation. Biochemistry, 30(14), 3576–3582.CrossRefPubMedGoogle Scholar
  30. 30.
    Brand, M. D., Harper, M. E., & Taylor, H. C. (1993). Control of the effective P/O ratio of oxidative phosphorylation in liver mitochondria and hepatocytes. Biochemical Journal, 291(Pt 3), 739–748.CrossRefPubMedPubMedCentralGoogle Scholar
  31. 31.
    Campos, J. C., Queliconi, B. B., Bozi, L. H. M., Bechara, L. R. G., Dourado, P. M. M., Andres, A. M., et al. (2017) Exercise reestablishes autophagic flux and mitochondrial quality control in heart failure. Autophagy. Scholar
  32. 32.
    Yu, T., Robotham, J. L., & Yoon, Y. (2006). Increased production of reactive oxygen species in hyperglycemic conditions requires dynamic change of mitochondrial morphology. Proceedings of the National Academy of Sciences of the United States of America, 103(8), 2653–2658.CrossRefPubMedPubMedCentralGoogle Scholar
  33. 33.
    Devi, T. S., Somayajulu, M., Kowluru, R. A., & Singh, L. P. (2017). TXNIP regulates mitophagy in retinal Muller cells under high-glucose conditions: Implications for diabetic retinopathy. Cell Death & Disease, 8(5), e2777.CrossRefGoogle Scholar
  34. 34.
    Stolen, T. O., Hoydal, M. A., Kemi, O. J., Catalucci, D., Ceci, M., Aasum, E., et al. (2009). Interval training normalizes cardiomyocyte function, diastolic Ca2+ control, and SR Ca2+ release synchronicity in a mouse model of diabetic cardiomyopathy. Circulation Research, 105(6), 527–536.CrossRefPubMedGoogle Scholar
  35. 35.
    Semeniuk, L. M., Kryski, A. J., & Severson, D. L. (2002). Echocardiographic assessment of cardiac function in diabetic db/db and transgenic db/db-hGLUT4 mice. American Journal of Physiology Heart and Circulatory Physiology, 283(3), H976–H982.CrossRefPubMedGoogle Scholar
  36. 36.
    Venardos, K., De Jong, K. A., Elkamie, M., Connor, T., & McGee, S. L. (2015). The PKD inhibitor CID755673 enhances cardiac function in diabetic db/db mice. PLoS ONE, 10(3), e0120934.CrossRefPubMedPubMedCentralGoogle Scholar
  37. 37.
    Anderson, E. J., Kypson, A. P., Rodriguez, E., Anderson, C. A., Lehr, E. J., & Neufer, P. D. (2009). Substrate-specific derangements in mitochondrial metabolism and redox balance in atrium of type 2 diabetic human heart. Journal of the American College of Cardiology, 54(20), 1891–1898.CrossRefPubMedPubMedCentralGoogle Scholar
  38. 38.
    Palmieri, V., Bella, J. N., Arnett, D. K., Liu, J. E., Oberman, A., Schuck, M. Y., et al. (2001). Effect of type 2 diabetes mellitus on left ventricular geometry and systolic function in hypertensive subjects: Hypertension Genetic Epidemiology Network (HyperGEN) study. Circulation, 103(1), 102–107.CrossRefPubMedGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2019

Authors and Affiliations

  • Fredrik H. Bækkerud
    • 1
    Email author
  • Simona Salerno
    • 1
  • Paola Ceriotti
    • 2
    • 3
  • Cecilie Morland
    • 4
  • Jon Storm-Mathisen
    • 5
  • Linda H. Bergersen
    • 6
    • 7
  • Morten A. Høydal
    • 8
    • 9
  • Daniele Catalucci
    • 2
    • 3
  • Tomas O. Stølen
    • 1
    • 8
    • 9
  1. 1.Department of Circulation and Medical Imaging, Faculty of Medicine and Health Science, K.G. Jebsen Centre of Exercise in MedicineNorwegian University of Science and TechnologyTrondheimNorway
  2. 2.Institute of Genetics and Biomedical Research, Milan UnitNational Research CouncilMilanItaly
  3. 3.Humanitas Clinical and Research CenterMilanItaly
  4. 4.Department of Pharmaceutical Biosciences, School of PharmacyUniversity of OsloOsloNorway
  5. 5.Division of Anatomy, Department of Molecular Medicine, Institute of Basic Medical Sciences, CMBN/SERTA Healthy Brain Ageing CentreUniversity of OsloOsloNorway
  6. 6.Department of Oral BiologyUniversity of OsloOsloNorway
  7. 7.Department of Neuroscience and Pharmacology, Center for Healthy AgingUniversity of CopenhagenCopenhagenDenmark
  8. 8.Group of Molecular and Cellular Cardiology, Department of Circulation and Medical Imaging, Faculty of Medicine and Health ScienceNorwegian University of Science and TechnologyTrondheimNorway
  9. 9.St. Olavs University HospitalTrondheimNorway

Personalised recommendations