Endurance Exercise Training Mitigates Diastolic Dysfunction in Diabetic Mice Independent of Phosphorylation of Ulk1 at S555

Guan, Yuntian; Zhang, Mei; Lacy, Christie; Shah, Soham; Epstein, Frederick H.; Yan, Zhen

doi:10.3390/ijms25010633

Open AccessArticle

Endurance Exercise Training Mitigates Diastolic Dysfunction in Diabetic Mice Independent of Phosphorylation of Ulk1 at S555

by

Yuntian Guan

^1,2,3,

Mei Zhang

^1,2,4,

Christie Lacy

¹,

Soham Shah

⁵,

Frederick H. Epstein

⁵ and

Zhen Yan

^{1,2,3,4,5,6,7,*}

¹

Fralin Biomedical Research Institute, Center for Exercise Medicine Research at Virginia Tech Carilion, Roanoke, VA 24016, USA

²

Center for Skeletal Muscle Research at Robert M. Berne Cardiovascular Research Center, University of Virginia, Charlottesville, VA 22903, USA

³

Departments of Pharmacology, School of Medicine, University of Virginia, Charlottesville, VA 22903, USA

⁴

Departments of Medicine, School of Medicine, University of Virginia, Charlottesville, VA 22903, USA

⁵

Departments of Biomedical Engineering, School of Medicine, University of Virginia, Charlottesville, VA 22903, USA

⁶

Departments of Molecular Physiology and Biological Physics, School of Medicine, University of Virginia, Charlottesville, VA 22903, USA

⁷

Department of Human Nutrition, Foods, and Exercise, College of Agriculture and Life Sciences, Virginia Tech, Blacksburg, VA 24061, USA

^*

Author to whom correspondence should be addressed.

Int. J. Mol. Sci. 2024, 25(1), 633; https://doi.org/10.3390/ijms25010633

Submission received: 8 November 2023 / Revised: 13 December 2023 / Accepted: 31 December 2023 / Published: 3 January 2024

(This article belongs to the Special Issue Molecular Insights into the Role of Exercise in Disease and Health)

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Abstract

Millions of diabetic patients suffer from cardiovascular complications. One of the earliest signs of diabetic complications in the heart is diastolic dysfunction. Regular exercise is a highly effective preventive/therapeutic intervention against diastolic dysfunction in diabetes, but the underlying mechanism(s) remain poorly understood. Studies have shown that the accumulation of damaged or dysfunctional mitochondria in the myocardium is at the center of this pathology. Here, we employed a mouse model of diabetes to test the hypothesis that endurance exercise training mitigates diastolic dysfunction by promoting cardiac mitophagy (the clearance of mitochondria via autophagy) via S555 phosphorylation of Ulk1. High-fat diet (HFD) feeding and streptozotocin (STZ) injection in mice led to reduced endurance capacity, impaired diastolic function, increased myocardial oxidative stress, and compromised mitochondrial structure and function, which were all ameliorated by 6 weeks of voluntary wheel running. Using CRISPR/Cas9-mediated gene editing, we generated non-phosphorylatable Ulk1 (S555A) mutant mice and showed the requirement of p-Ulk1at S555 for exercise-induced mitophagy in the myocardium. However, diabetic Ulk1 (S555A) mice retained the benefits of exercise intervention. We conclude that endurance exercise training mitigates diabetes-induced diastolic dysfunction independent of Ulk1 phosphorylation at S555.

Keywords: diabetes; diastolic dysfunction; exercise intervention; mitophagy; mitochondrial quality; echocardiography

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MDPI and ACS Style

Guan, Y.; Zhang, M.; Lacy, C.; Shah, S.; Epstein, F.H.; Yan, Z. Endurance Exercise Training Mitigates Diastolic Dysfunction in Diabetic Mice Independent of Phosphorylation of Ulk1 at S555. Int. J. Mol. Sci. 2024, 25, 633. https://doi.org/10.3390/ijms25010633

AMA Style

Guan Y, Zhang M, Lacy C, Shah S, Epstein FH, Yan Z. Endurance Exercise Training Mitigates Diastolic Dysfunction in Diabetic Mice Independent of Phosphorylation of Ulk1 at S555. International Journal of Molecular Sciences. 2024; 25(1):633. https://doi.org/10.3390/ijms25010633

Chicago/Turabian Style

Guan, Yuntian, Mei Zhang, Christie Lacy, Soham Shah, Frederick H. Epstein, and Zhen Yan. 2024. "Endurance Exercise Training Mitigates Diastolic Dysfunction in Diabetic Mice Independent of Phosphorylation of Ulk1 at S555" International Journal of Molecular Sciences 25, no. 1: 633. https://doi.org/10.3390/ijms25010633

APA Style

Guan, Y., Zhang, M., Lacy, C., Shah, S., Epstein, F. H., & Yan, Z. (2024). Endurance Exercise Training Mitigates Diastolic Dysfunction in Diabetic Mice Independent of Phosphorylation of Ulk1 at S555. International Journal of Molecular Sciences, 25(1), 633. https://doi.org/10.3390/ijms25010633

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Endurance Exercise Training Mitigates Diastolic Dysfunction in Diabetic Mice Independent of Phosphorylation of Ulk1 at S555

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