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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
Article

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.

Keywords

Mitochondria Exercise training Diabetes Diabetic cardiomyopathy 

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

Notes

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.

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).

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)

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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

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