Abstract
Exercise capacity during aging is strongly linked to life quality, morbidity and mortality. In a selectively-bred rat model of intrinsic aerobic phenotypes, low-capacity (LCR) compared to high-capacity running (HCR) rats exhibit increased rates of metabolic syndrome, adiposity, dyslipidemia, endothelial dysfunction, and insulin resistance. Previously, we showed that with aging HCR rats present greater mitochondrial turnover underlying higher cardiomyocyte energetic performance, sustained by preferential selection of lipids oxidation with improved control of acetyl-CoA (AcCoA) concentration. All these positive indexes decline with aging, but they are better preserved in HCR vs. LCR, parallel with healthier aging and extended longevity. To investigate systemic metabolism in main organs supplying substrates (fatty acids, glucose, ketone bodies) to the heart, untargeted metabolomics was performed in liver and serum of young and middle age female HCR and LCR rats. Multivariate statistics indicated a metabolome pattern in liver comprised by higher abundance of fatty acids (e.g., palmitic, palmitoleic, oleic) at similar levels of intermediates from glucose metabolism in HCR vs. LCR. As a function of age, the serum of HCR rats exhibited an enrichment in fatty acids (e.g., linoleic, palmitic, arachidic) consistent with the changes observed in liver's metabolome. Higher liver AMP levels in HCR vs. LCR suggest activation of AMPK signaling, in agreement with the enhanced autophagy/mitophagy observed in HCR. Importantly, the higher relative LCR/HCR fold-changes of acetylated intermediates, in both liver and serum, agrees with the idea of widespread increased acetylation, compatible with the higher concentration of AcCoA measured in cardiomyocytes from LCR vs. HCR. Metabolomics reveal systemic, organ-concerted (liver-serum-heart), metabolic remodeling compatible with higher energetic performance, better preserved mitochondrial turnover, preferential lipid oxidation, and improved control of acetylation in HCR leading to extended longevity and better functional capacity.
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