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Exercise enhances cardiac function by improving mitochondrial dysfunction and maintaining energy homoeostasis in the development of diabetic cardiomyopathy

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Diabetic cardiomyopathy (DCM) is a major cause of morbidity and mortality in diabetic patients. Reactive oxygen species (ROS) produced by oxidative stress play an important role in the development of DCM. DCM involves abnormal energy metabolism, thereby reducing energy production. Exercise has been reported to be effective in protecting the heart against ROS accumulation during the development of DCM. We hypothesize that the AMPK/PGC-1α axis may play a crucial role in exercise-induced bioenergetic metabolism and aerobic respiration on oxidative stress parameters in the development of diabetic cardiomyopathy. Using a streptozotocin/high-fat diet mouse to generate a diabetic model, our aim was to evaluate the effects of exercise on the cardiac function, mitochondrial oxidative capacity, mitochondrial function, and cardiac expression of PGC-1α. Mice fed a high-fat diet were given MO-siPGC-1α or treated with AMPK inhibitor. Mitochondrial structure and effects of switching between the Warburg effect and aerobic respiration were analysed. Exercise improved blood pressure and systolic dysfunction in diabetic mouse hearts. The beneficial effects of exercise were also observed in a mitochondrial function study, as reflected by an enhanced oxidative phosphorylation level, increased membrane potential, and decreased ROS level and oxygen consumption. On the other hand, depletion of PGC-1α attenuated the effects of exercise on the enhancement of mitochondrial function. In addition, PGC-1α may be responsible for reversing the Warburg effect to aerobic respiration, thus enhancing mitochondrial metabolism and energy homoeostasis. In this study, we demonstrate the protective effects of exercise on shifting energy metabolism from fatty acid oxidation to glucose oxidation in an established diabetic stage. These data suggest that exercise is effective at ameliorating diabetic cardiomyopathy by improving mitochondrial function and reducing metabolic disturbances.

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Diabetic cardiomyopathy

PGC-1α :

Peroxisome proliferator-activated receptor gamma coactivator 1-α


AMP-activated protein kinase




Carnitine palmitoyltransferase 1α


Peroxisome proliferator-activated receptor-γ coactivator


Morpholino (MO)-based oligos to inhibit PGC-1α translation


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This work was financially supported through grants from the National Natural Science Foundation (Project Numbers: 81800269; 81800362; 81670373; 81670459), the National Key R&D Program of China (2016YFC1301100), and Young Innovative Talents Training Plan of General Undergraduate Colleges and Universities of Heilongjiang Province (UNPYSCT-2018074).

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Correspondence to Wei Cao or Jingjin Liu.

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Exercise Ameliorates Cardiac Dysfunction by Decreasing ROS Production.

Exercise enhances the mitochondrial oxidative capacity in the diabetic heart.

Exercise shifts energy metabolism from fatty acid oxidation to glucose oxidation.

Exercise regulates cardiac energy metabolism switching through activation of PGC-1α.

Exercise maintains metabolic homeostasis through an AMPK/PGC-1α-dependent circuit.

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Wang, S.Y., Zhu, S., Wu, J. et al. Exercise enhances cardiac function by improving mitochondrial dysfunction and maintaining energy homoeostasis in the development of diabetic cardiomyopathy. J Mol Med 98, 245–261 (2020). https://doi.org/10.1007/s00109-019-01861-2

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  • Diabetic cardiomyopathy
  • Exercise
  • Mitochondrial dysfunction
  • Energy metabolism
  • PGC-1α