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Untargeted metabolomics analysis of ischemia–reperfusion-injured hearts ex vivo from sedentary and exercise-trained rats

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Abstract

Introduction

The effects of exercise on the heart and its resistance to disease are well-documented. Recent studies have identified that exercise-induced resistance to arrhythmia is due to the preservation of mitochondrial membrane potential.

Objectives

To identify novel metabolic changes that occur parallel to these mitochondrial alterations, we performed non-targeted metabolomics analysis on hearts from sedentary and exercise-trained rats challenged with isolated heart ischemia–reperfusion injury (I/R).

Methods

Eight-week old Sprague–Dawley rats were treadmill trained 5 days/week for 6 weeks (exercise duration and intensity progressively increased to 1 h at 30 m/min up a 10.5% incline, 75–80% VO2max). The recovery of pre-ischemic function for sedentary rat hearts was 28.8 ± 5.4% (N = 12) compared to exercise trained hearts, which recovered 51.9% ± 5.7 (N = 14) (p < 0.001).

Results

Non-targeted GC–MS metabolomics analysis of (1) sedentary rat hearts; (2) exercise-trained rat hearts; (3) sedentary rat hearts challenged with global ischemia–reperfusion (I/R) injury; and (4) exercise-trained rat hearts challenged with global I/R (10/group) revealed 15 statistically significant metabolites between groups by ANOVA using Metaboanalyst (p < 0.001). Enrichment analysis of these metabolites for pathway-associated metabolic sets indicated a > 10-fold enrichment for ammonia recycling and protein biosynthesis. Subsequent comparison of the sedentary hearts post-I/R and exercise-trained hearts post-I/R further identified significant differences in three metabolites (oleic acid, pantothenic acid, and campesterol) related to pantothenate and CoA biosynthesis (p ≤ 1.24E−05, FDR ≤ 5.07E−4).

Conclusions

These studies shed light on novel mechanisms in which exercise-induced cardioprotection occurs in I/R that complement both the mitochondrial stabilization and antioxidant mechanisms recently described. These findings also link protein synthesis and protein degradation (protein quality control mechanisms) with exercise-linked cardioprotection and mitochondrial susceptibility for the first time in cardiac I/R.

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Abbreviations

AF:

Aortic flow

CF:

Coronary flow

CoA:

Coenzyme A

CO:

Cardiac output

I/R:

Ischemia/reperfusion

PC:

Principal component

PCA:

Principal components analysis

SOD:

Superoxide dismutase

SP:

Peak systolic pressure

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Acknowledgements

This work was supported by the National Institutes of Health (R01HL104129 to MSW), the Leducq Foundation Transatlantic Networks of Excellence (11CVD04 to MSW and CP), and the American Heart Association (Post-Doctoral Fellowship to TP).

Author information

Author notes

  1. Traci L. Parry and Joseph W. Starnes have contributed equally to this study.

Authors and Affiliations

  1. McAllister Heart Institute, University of North Carolina, Chapel Hill, NC, USA

    Traci L. Parry & Monte S. Willis

  2. Department of Pathology & Laboratory Medicine, University of North Carolina, 111 Mason Farm Road, MBRB 2340B, Chapel Hill, NC, 27599, USA

    Traci L. Parry & Monte S. Willis

  3. Department of Kinesiology, University of North Carolina at Greensboro, Greensboro, NC, USA

    Joseph W. Starnes & Peter Christopher

  4. Sarah W. Stedman Nutrition and Metabolism Center, Duke Molecular Physiology Institute, Duke University Medical Center, Durham, NC, USA

    Sara K. O’Neal, James R. Bain, Michael J. Muehlbauer & Amro Ilaiwy

  5. Division of Endocrinology, Metabolism, and Nutrition, Department of Medicine, Duke University Medical Center, Durham, NC, USA

    James R. Bain & Amro Ilaiwy

  6. Toxicology Curriculum, University of North Carolina, Chapel Hill, NC, USA

    Aubree Honcoop

  7. Presbyterian Hospital/Weill-Cornell Medical Center, New York, NY, USA

    Cam Patterson

  8. Department of Pharmacology, University of North Carolina, Chapel Hill, NC, USA

    Monte S. Willis

Authors
  1. Traci L. Parry
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  2. Joseph W. Starnes
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  3. Sara K. O’Neal
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  10. Monte S. Willis
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Contributions

TP, JS, and MW conceived and designed the experiments; TP, JS, AH, PH, JB, MM, and AI performed the experiments, SO, JB, MM, and MW were involved in the analysis and interpretation of the data, and JS, TP, and MW wrote the draft manuscript. TP, JS, SO, JB, MM, AH, AI, PC, CP, and MW edited and revised the manuscript.

Corresponding author

Correspondence to Monte S. Willis.

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Conflict of interest

The authors declare that they have no conflict of interest.

Ethical approval

This investigation was approved by the UNC-Greensboro’s Animal Care and Use Committee and conforms to the Guide for the Care and Use of Laboratory Animals published by the National Institutes of Health (NIH Publication No. 85–23, Revised 1996). All applicable international, national, and/or institutional guidelines for the care and use of animals were followed.

Electronic supplementary material

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11306_2017_1303_MOESM1_ESM.pdf

Supplemental Fig. 1. Heatmap analysis of all named metabolites from all individual rat hearts from all four groups (exercise trained, exercise trained post-ischemia reperfusion, sedentary, sedentary post-ischemia reperfusion) included in the ANOVA analysis of significance. N = 10 biological replicates/group.

Supplemental Fig. 2. Heatmap analysis of all named metabolites from all individual rat hearts included in the t test analysis of significance (sedentary I/R vs. exercise trained I/R). N = 10 biological replicates/group.

Supplemental Fig. 3. Peak value comparisons of ANOVA significant metabolites involved in the citric acid cycle in sedentary and exercise trained hearts ± ischemia reperfusion injury. Peak values of (A) Glucose (and other aldohexoses), and (B) Glucose-6-phosphate from rat hearts after sedentary, exercise trained, sedentary ischemia reperfusion injury, and exercise trained reperfusion injury. An ANOVA was run to determine significance, followed by a post-hoc Fisher’s Least Significant Difference (LSD) multiple comparison between groups. N = 10 biological replicates/group. *p < 0.05 versus to I/R, **p  < 0.05 versus exercise,#p < 0.05 versus exercise I/R. Data is presented as the mean ± SEM.

Spplemental Fig. 4. Peak value comparisons of t test significant metabolites identified by comparing sedentary I/R and exercise trained I/R. Peak values of (A) Oleic acid, (B) Pantothenic acid, and (C) Campesterol from rat hearts after sedentary, exercise trained, sedentary ischemia reperfusion injury, and exercise trained reperfusion injury. Although these metabolites were identified by t test significance, this graph presents their ANOVA statistics from the initial analysis (i.e., both t test and ANOVA significant). An ANOVA was run to determine significance, followed by a post-hoc Fisher’s Least Significant Difference (LSD) multiple comparison between groups. N = 10 biological replicates/group. *p  < 0.05 versus to I/R, **p < 0.05 versus exercise, #p  < 0.05 versus exercise I/R. Data is presented as the mean ± SEM.

Supplemental Fig. 5. Enrichment analysis of t test significant metabolites comparing sedentary I/R versus exercise trained I/R. Enrichment analysis was performed using Metaboanalyst, comparing to (A) Pathway associated metabolite sets, (B) Predicted Metabolite sets, and (C) Enrichment of Location-based metabolite sets. (PDF 1586 KB)

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Parry, T.L., Starnes, J.W., O’Neal, S.K. et al. Untargeted metabolomics analysis of ischemia–reperfusion-injured hearts ex vivo from sedentary and exercise-trained rats. Metabolomics 14, 8 (2018). https://doi.org/10.1007/s11306-017-1303-y

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