Alpha-7 nicotinic and muscarinic acetylcholine receptor agonists promote a favorable pattern of cardiac metabolic reprogramming in doxorubicin-induced heart failure rats

Sympathetic hyperactivation and metabolic reprogramming are found in heart failure. Parasympathetic activation by acetylcholine receptor agonists attenuates doxorubicin-induced heart failure by improving mitochondrial function and ameliorating apoptosis and inflammation. However, the effect of these agents on cardiac metabolic reprogramming in doxorubicin-induced heart failure has never been investigated. Male Wistar rats received either vehicle, 6 doses of 3 mg/kg/day of doxorubicin, 6 doses of 3 mg/kg/day of doxorubicin and 3 mg/kg/day of an alpha-7 nicotinic acetylcholine receptor agonist for 30 days, or 6 doses of 3 mg/kg/day of doxorubicin and 12 mg/kg/day of a muscarinic acetylcholine receptor agonist for 30 days. Then, the rats were euthanized to collect heart and serum for metabolomics study. Doxorubicin caused increased glycolysis, increased ketone body utilization, decreased fat utilization, decreased succinate oxidation, and decreased adenosine triphosphate production. Co-treatment with acetylcholine receptor agonist ameliorated an increase in glycolysis, and restored fat utilization, succinate oxidation, and adenosine triphosphate production in the heart. Metabolome alterations in serum were consistent with those in the heart. Our findings highlighted the roles of metabolomics in identifying cardiac metabolic reprogramming and emphasized the potential of acetylcholine receptor agonist in promoting a favorable pattern of cardiac metabolic reprogramming in doxorubicin-induced heart failure.