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

ABSTRACT: The effects of exercise on the heart and its resistance to disease are well-documented. Recent studies have identified exercise-induced resistance to arrhythmia is due to the preservation of mitochondrial membrane potential. To identify novel metabolic changes that occurred parallel to these mitochondrial alterations, we performed non-targeted metabolomics analysis on hearts from sedentary (Sed) and exercise- trained (Ex) rats challenged with isolated heart ischemia-reperfusion injury (I/R). Eight weeks old Sprague- Dawley rats were treadmill trained five days/week for six weeks (exercise duration and intensity progressively increased to 1 hour at 30 m/min up to 10.5% incline, 75-80% VO2mx). 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). 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 challeged with global I/R (10/group) revealed 20 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 (L-Glutamic acid; L-Proline; L-Histidine; L-Serine; L-Aspartic acid; L-Glutamine)(p<=4.05E-05, FDR=0.0024). Subsequent comparison of the sedentary hearts post-I/R and exercise-trained hearts post-I/R further identified significant differences in metabolites related to Aminoacyl-tRNA biosynthesis and nitrogen metabolism (4) (p<=1.24E-05, FDR<=5.07E-4). These studies shed light on novel mechanisms in which exercise-induced cardioprotection occurs in I/R which 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.

ORGANISM(S): Rat Rattus Norvegicus

TISSUE(S): Muscle

DISEASE(S): Heart Injury

SUBMITTER: Monte Willis

PROVIDER: ST000897 | MetabolomicsWorkbench | Sat May 20 00:00:00 BST 2017

REPOSITORIES: MetabolomicsWorkbench

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Project description:Purpose: Aerobic capacity is a strong predictor of cardiovascular mortality. To determine the relationship between inborn aerobic capacity and soleus gene expression we examined genome-wide gene expression in soleus muscle of rats artificially selected for high and low running capacity (HCR and LCR, respectively) over 16 generations. The artificial selection of LCR caused accumulation of risk factors of cardiovascular disease similar to the metabolic syndrome seen in man, whereas HCR had markedly better cardiac function. We also studied alterations in gene expression in response to exercise training in the two groups, since accumulating evidence indicates that exercise has profound beneficial effects on the metabolic syndrome. Methods:; Soleus gene expression of both sedentary and exercise trained HCR and LCR was characterized by microarray- and gene ontology analysis. Results: Although HCR and LCR had an inborn 347% difference in running capacity, only three genes were found differentially expressed in the soleus muscle between the two groups. Up-regulation of the mitochondrial enzyme leucyl-transferRNA synthetase (LARS2) was found in the sedentary LCR. Increased expression of LARS2 has been associated with a mitochondrial DNA mutation linked to maternally inherited diabetes and mitochondrial dysfunction. In line with our findings, a growing body of evidence suggests that LCR have compromised mitochondrial function. After exercise training, 58 genes were altered in the soleus muscle of HCR, in contrast to only one in the LCR group. This suggests that animals born with different levels of fitness respond different to the same type of exercise training. Adaptations to exercise in HCR seemed to be associated with increased lipid metabolism and fatty acid elongation in the mitochondria. Also, genes associated with the peroxisomes, seemed to be central in the adaptation to exercise. Conclusion: The results indicate that (i) LCR might have mitochondrial dysfunction, which may be a contributing factor of the low inborn aerobic capacity, (ii) animals born with different levels of fitness respond different to the same exercise program. Experiment Overall Design: There are 16 samples in this study.

Project description:Exercise has multi-systemic benefits and attenuates the physiological impairments associated with aging. Emerging evidence suggests that circulating exosomes mediate some of the beneficial effects of exercise via the transfer of microRNAs between tissues. However, the impact of regular exercise and acute exercise on circulating exosomal microRNAs (exomiRs) in older populations remains unknown. In the present study, we analyzed circulating exomiR expression in endurance-trained elderly men and age-matched sedentary males at baseline (Pre), immediately after a forty minute bout of aerobic exercise on a cycle ergometer (Post), and three hours after this acute exercise (3hPost). Plasma exosomes were isolated, characterized, and exomiR levels were determined by sequencing. The effect of regular exercise on circulating exomiRs was assessed using paired t-tests of baseline expression levels in the trained and sedentary groups. The effect of acute exercise was determined by comparing baseline and post-training expression levels in each group. Regular exercise resulted in significantly increased baseline expression of three exomiRs (miR-486-5p, miR-215-5p, miR-941) and decreased expression of one exomiR (miR-151b). Acute exercise altered circulating exomiR expression in both groups. However, exomiRs regulated by acute exercise in the trained group (7 miRNAs at Post and 8 at 3hPost) were distinct from those in the sedentary group (9 at Post and 4 at 3hPost). Pathway analysis prediction and reported target validation experiments revealed that the majority of exercise-regulated exomiRs are targeting genes that are related to IGF-1 signaling, a pathway involved in exercise-induced muscle and cardiac hypertrophy. The immediately post-acute exercise exomiR signature in the trained group correlates with activation of IGF-1 signaling, whereas in the sedentary group it is associated with inhibition of IGF-1 signaling. These results suggest that training status may counteract age-related anabolic resistance by modulating circulating exomiR profiles both at baseline and in response to acute exercise.

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

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