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

Traci L. Parry, Joseph W. Starnes, Sara K. O’Neal, James R. Bain, Michael J. Muehlbauer, Aubree Honcoop, Amro Ilaiwy, Peter Christopher, Cam Patterson, Monte Willis

Research output: Contribution to journalArticle

2 Citations (Scopus)

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.

Original languageEnglish (US)
Article number8
JournalMetabolomics
Volume14
Issue number1
DOIs
StatePublished - Jan 1 2018
Externally publishedYes

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Metabolomics
Heart Injuries
Rats
Pantothenic Acid
Biosynthesis
Disease Resistance
Mitochondrial Membrane Potential
Recycling
Protein Biosynthesis
Coenzyme A
Oleic Acid
Ammonia
Quality Control
Proteolysis
Cardiac Arrhythmias
Antioxidants
Exercise equipment
Proteins
Metabolites
Wounds and Injuries

Keywords

  • Cardioprotection
  • Exercise
  • Ischemia/reperfusion injury
  • Metabolism

ASJC Scopus subject areas

  • Endocrinology, Diabetes and Metabolism
  • Biochemistry
  • Clinical Biochemistry

Cite this

Untargeted metabolomics analysis of ischemia–reperfusion-injured hearts ex vivo from sedentary and exercise-trained rats. / Parry, Traci L.; Starnes, Joseph W.; O’Neal, Sara K.; Bain, James R.; Muehlbauer, Michael J.; Honcoop, Aubree; Ilaiwy, Amro; Christopher, Peter; Patterson, Cam; Willis, Monte.

In: Metabolomics, Vol. 14, No. 1, 8, 01.01.2018.

Research output: Contribution to journalArticle

Parry, TL, Starnes, JW, O’Neal, SK, Bain, JR, Muehlbauer, MJ, Honcoop, A, Ilaiwy, A, Christopher, P, Patterson, C & Willis, M 2018, 'Untargeted metabolomics analysis of ischemia–reperfusion-injured hearts ex vivo from sedentary and exercise-trained rats', Metabolomics, vol. 14, no. 1, 8. https://doi.org/10.1007/s11306-017-1303-y
Parry, Traci L. ; Starnes, Joseph W. ; O’Neal, Sara K. ; Bain, James R. ; Muehlbauer, Michael J. ; Honcoop, Aubree ; Ilaiwy, Amro ; Christopher, Peter ; Patterson, Cam ; Willis, Monte. / Untargeted metabolomics analysis of ischemia–reperfusion-injured hearts ex vivo from sedentary and exercise-trained rats. In: Metabolomics. 2018 ; Vol. 14, No. 1.
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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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AU - Starnes, Joseph W.

AU - O’Neal, Sara K.

AU - Bain, James R.

AU - Muehlbauer, Michael J.

AU - Honcoop, Aubree

AU - Ilaiwy, Amro

AU - Christopher, Peter

AU - Patterson, Cam

AU - Willis, Monte

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N2 - 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.

AB - 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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KW - Ischemia/reperfusion injury

KW - Metabolism

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