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

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Abstract

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.

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Availability of Data and Material

The datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request.

Abbreviations

A:

Late LV filling

C:

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

E:

Early LV filling

E′:

Myocardial velocity

EF:

Ejection fraction

ETC:

Electron transport chain

HIIT:

High intensity interval training

IDH:

Isocitrate dehydrogenase

LV:

Left ventricle

MCU:

Mitochondrial calcium uniporter

OGDH:

Oxoglutarate dehydrogenase

OXPHOS:

Oxidative phosphorylation

PGC1-α:

Peroxisome proliferator-activated receptor gamma coactivator 1-alpha

PPARγ:

Peroxisome proliferator-activated receptorγ

SDH:

Succinate dehydrogenase

T2DM:

Type 2 diabetes mellitus

TFAM:

Mitochondrial transcription factor A

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Funding

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).

Author information

Author notes

  1. Daniele Catalucci and Tomas O. Stølen contributed equally to this work.

Authors and Affiliations

  1. Department of Circulation and Medical Imaging, Faculty of Medicine and Health Science, K.G. Jebsen Centre of Exercise in Medicine, Norwegian University of Science and Technology, Postboks 8905, 7491, Trondheim, Norway

    Fredrik H. Bækkerud, Simona Salerno & Tomas O. Stølen

  2. Institute of Genetics and Biomedical Research, Milan Unit, National Research Council, 20138, Milan, Italy

    Paola Ceriotti & Daniele Catalucci

  3. Humanitas Clinical and Research Center, Rozzano, 20089, Milan, Italy

    Paola Ceriotti & Daniele Catalucci

  4. Department of Pharmaceutical Biosciences, School of Pharmacy, University of Oslo, Oslo, Norway

    Cecilie Morland

  5. Division of Anatomy, Department of Molecular Medicine, Institute of Basic Medical Sciences, CMBN/SERTA Healthy Brain Ageing Centre, University of Oslo, Oslo, Norway

    Jon Storm-Mathisen

  6. Department of Oral Biology, University of Oslo, Oslo, Norway

    Linda H. Bergersen

  7. Department of Neuroscience and Pharmacology, Center for Healthy Aging, University of Copenhagen, Copenhagen, Denmark

    Linda H. Bergersen

  8. Group of Molecular and Cellular Cardiology, Department of Circulation and Medical Imaging, Faculty of Medicine and Health Science, Norwegian University of Science and Technology, Trondheim, Norway

    Morten A. Høydal & Tomas O. Stølen

  9. St. Olavs University Hospital, Trondheim, Norway

    Morten A. Høydal & Tomas O. Stølen

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  1. Fredrik H. Bækkerud
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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.

Corresponding author

Correspondence to Fredrik H. Bækkerud.

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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.

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Handling Editor: Y. James Kang.

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12012_2019_9514_MOESM1_ESM.tif

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

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

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

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)

Supplementary Table 1 (DOCX 13 KB)

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Bækkerud, F.H., Salerno, S., Ceriotti, P. et al. High Intensity Interval Training Ameliorates Mitochondrial Dysfunction in the Left Ventricle of Mice with Type 2 Diabetes. Cardiovasc Toxicol 19, 422–431 (2019). https://doi.org/10.1007/s12012-019-09514-z

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