A p53-mediated repression of the PGC1⍺ and apelin receptor signalling pathways limit fatty acid oxidation energetics; implications for anthracycline-induced cardiotoxicity

To identify potential metabolic pathways that may be altered by anthracyclines, we treated lung cancer mice for several weeks with the anthracycline doxorubicin, which induced p53 and caused cardiac dysfunction. We then isolated intact cardiomyocytes from the myocardium and performed unbiased RNA sequencing. As predicted, a number of DNA damaging and apoptosis-related genes (many of which are p53 regulated) were significantly induced, while cardiomyocyte survival and maintenance genes were predictably suppressed in cardiomyocytes from doxorubicin-treated mice, compared to controls. Intriguingly, our sequencing analysis identified only one metabolic pathway that was different between the two groups, and this was suppression of the apelin receptor (APLNR) signalling pathway (which can increase fatty acid oxidation (FAO), in doxorubicin-treated mice.