Differential Effects of Beta-Hydroxybutyrate Enantiomers on Induced Pluripotent Stem Derived Cardiac Myocyte Electrophysiology

Beta-hydroxybutyrate (beta OHB), along with acetoacetate and acetone, are liver-produced ketone bodies that are increased after fasting or prolonged exercise as an alternative fuel source to glucose. beta OHB, as the main circulating ketone body, is not only a G-protein coupled receptor ligand but also a histone deacetylases inhibitor, prompting the reexamination of its role in health and disease. In this study, we compared the effects of two commercial beta OHB formulations an enantiomer R beta OHB and a racemic mixture +/-beta OHB on induced pluripotent stem cell cardiac myocytes (iPS-CMs) electrophysiology. Cardiac myocytes were cultured in R beta OHB or +/-beta OHB for at least ten days after lactate selection. Flouvolt or Fluo-4 was used to assay iPS-CMs electrophysiology. We found that while both formulations increased the optical potential amplitude, R beta OHB prolonged the action potential duration but +/-beta OHB shortened the action potential duration. Moreover, +/-beta OHB increased the peak calcium transient but R beta OHB reduced the peak calcium transient. Co-culturing with glucose or fatty acids did not ameliorate the effects, suggesting that beta OHB was more than a fuel source. The effect of beta OHB on iPS-CMs electrophysiology is most likely stereoselective, and care must be taken to evaluate the role of exogenous beta OHB in health and disease.

Automated summary

Beta-hydroxybutyrate (beta OHB) is a liver-produced ketone body that serves as an alternative fuel source to glucose, especially during fasting or prolonged exercise. This study compared the effects of two commercial beta OHB formulations on the electrophysiology of induced pluripotent stem cell cardiac myocytes (iPS-CMs). The results showed that these formulations had different effects on the electrophysiology, possibly due to their stereoselectivity.