Left ventricle transcriptomic analysis reveals connective tissue accumulation associates with initial age-dependent decline in V̇o2peak from its lifetime apex

Abstract

Peak oxygen consumption (V̇o2peak) strongly predicts morbidity and mortality better than other established risk factors, yet mechanisms associated with its age-associated decline are unknown. Our laboratory has shown that V̇o2peak first begins to decrease at the same age of 19–20 wk in both sedentary and wheel-running, female Wistar rats (Toedebusch et al., Physiol Genomics. 48: 101–115, 2016). Here, we employed a total systemic approach using unsupervised interrogation of mRNA with RNA sequencing. The purpose of our study was to analyze transcriptomic profiles from both sedentary (SED) and wheel-running (RUN) conditions as a strategy to identify pathways in the left ventricle that may contribute to the initial reductions in V̇o2peak occurring between 19 and 27 wk of age. Transcriptomic comparisons were made within both SED and RUN rats between 19 and 27 wk ( n = 5–8). Analysis of mRNAs shared in SED and RUN between 19 and 27 wk found 17 upregulated (e.g., Adra1d, Rpl17, Xpo7) and 8 downregulated (e.g., Cdo1, Ctfg, Sfrp1) mRNAs, at 19 wk, respectively. Furthermore, bioinformatics analysis of mRNAs common to SED and RUN produced networks suggestive of increased connective tissue development at 27 vs. 19 wk. Additionally, Ctfg mRNA was negatively associated with V̇o2peak in both SED and RUN ( P < 0.05). In summary, transcriptomic analysis revealed mRNAs and networks associated with increased connective tissue development, decreased α-adrenergic activity, and decreased protein translation in the left ventricle that could, in part, potentially influence the initiation of the lifelong reduction in V̇o2peak, independent of physical activity levels.