Beta-aminoisobutyric acid attenuates doxorubicin-induced cardiotoxicity through the adenosine 5′-monophosphate-activated protein kinase-mediated pathway

In this study, the adenosine 5'-monophosphate-activated protein kinase (AMPK)-dependent mechanisms underlying the effect of β-aminoisobutyric acid (BAIBA), an exercise-induced myokine, in mitigating doxorubicin (DOX)-induced cardiotoxicity were investigated.In <i>vitro/vivo</i> DOX-induced injury models were constructed, and their cardiac functions were detected by echocardiography/histology. Moreover, serum biomarkers including lactate dehydrogenase (LDH), creatine kinase-myocardial band (CK-MB), and brain natriuretic peptide (BNP) were measured. The mitochondrial ultrastructure was examined by transmission electron microscopy (TEM), and the generation of reactive oxygen species (ROS) was checked by MitoSOX^™ Red staining. The analysis results showed that BAIBA significantly preserved the cardiac systolic function, reduced myocardial damage, and attenuated mitochondrial dysfunction, as evidenced by maintained cristae integrity and suppressed ROS overproduction. The mechanism was that BAIBA enhanced cardiac AMPK phosphorylation, while dorsomorphin abrogated the antioxidant effects of AMPK through inhibiting its activation.The findings demonstrate that BAIBA counteracts DOX cardiotoxicity <i>via</i> AMPK-mediated mitochondrial bioenergetic preservation. It provides a novel cardioprotective therapy as an exercise-mimetic adjuvant.