Proteomic analysis reveals perturbed energy metabolism and elevated oxidative stress in hearts of rats with inborn low aerobic capacity

Abstract

Selection on running capacity has created rat phenotypes of high capacity runners (HCR) that have enhanced cardiac function and low capacity runners (LCR) that exhibit risk factors of metabolic syndrome. We analysed hearts of HCR and LCR from generation 22 of selection using DIGE and identified proteins from MS database searches. The running capacity of HCR was 6-fold greater than LCR. DIGE resolved 957 spots and proteins were unambiguously identified in 369 spots. Protein expression profiling detected 67 statistically significant (P<0.05; false discovery rate <10 %, calculated using q-values) differences between HCR and LCR. Hearts of HCR rats exhibited robust increases in the abundance of each enzyme of the beta-oxidation pathway. In contrast, LCR hearts were characterised by the modulation of enzymes associated with ketone body or amino acid metabolism. LCR also exhibited enhanced expression of antioxidant enzymes such as catalase and greater phosphorylation of alpha B-crystallin at serine 59, which is a common point of convergence in cardiac stress signalling. Thus proteomic analysis revealed selection on low running capacity is associated with perturbations in cardiac energy metabolism and provided the first evidence that the LCR cardiac proteome is exposed to greater oxidative stress.

Label‐free profiling of white adipose tissue of rats exhibiting high or low levels of intrinsic exercise capacity

“…Accordingly, antioxidant enzymes, including superoxide dismutase, peroxiredoxin 6, and glutathione S‐transferase were significantly less abundant in LCR. This finding is consistent with the greater oxidative stress reported in the kidneys , liver , skeletal muscle , and heart of LCR rats and further highlights oxidative stress as a common process associated with low aerobic capacity. Herein nontargeted proteomics also detected a significantly greater (43%) abundance of mitogen‐activated protein kinase 3 (ERK1), which is commonly activated in adipocytes exposed to pharmacologically induced ER stress or inflammatory cytokines .…”

Maximal Oxidative Capacity during Exercise Is Associated with Skeletal Muscle Fuel Selection and Dynamic Changes in Mitochondrial Protein Acetylation

“…Previous studies have demonstrated increased mRNA and protein expression in pathways related to oxidative metabolism in HCR vs. LCR (Burniston et al, 2011; Kivela et al, 2010). To investigate potential changes in the proteome and post-translation modifications in skeletal muscle mitochondria with exercise, we performed quantitative proteomic analysis.…”

Low intrinsic exercise capacity in rats predisposes to age-dependent cardiac remodeling independent of macrovascular function

“…These findings raise the possibility that impaired microvascular perfusion is a contributing factor to the cardiac phenotype associated with an inherited low capacity for exercise. Previous proteomic and array studies (3,4) suggested that LCR may exhibit a predisposition for LV remodeling, but those studies focused on older animals (30 -50 wk of age). Confirmation of morphological changes specifically on LV histology, protein content, or gene expression using real-time PCR or other semiquantitative approaches was not available.…”

“…While this may be a result of concomitant impairments in endothelial nitric oxide (NO)-dependent relaxation (49), endothelial function has yet to be studied in the LCR microvasculature. Skeletal muscle impairments are also evident in LCR with regard to insulin sensitivity, responsiveness to ␤-adrenoceptor activation, and levels of key proteins for mitochondrial function (3,20,26). Modest but significant impairments in myocardial systolic and diastolic function are observed in cardiomyocytes isolated from LCR compared with HCR rats (49).…”