β-hydroxybutyrate is the primary ketone body produced by the body during ketosis and is used to meet its metabolic demands. The healthy adult heart derives most of its energy from fatty acid oxidation. However, in certain diseases, the heart alters its substrate preference and increases its ketone body metabolism. Little is known about the effects of βOHB on ventricular myocyte excitation-contraction coupling. Therefore, we examined the effects of ketone body metabolism on single cell excitation-contraction coupling during normoxic and hypoxic conditions. Myocytes were isolated from adult rats, cultured for 18 h in RPMI 1640, RPMI 1640 no glucose, and M199, HEPES with/without various amount of βOHB added. To simulate hypoxia, myocytes were incubated at 1%O2, 5% CO2 for 1 h followed by incubation at atmospheric oxygen (21%O2,5% CO2) for 30 min before recordings. Recordings were obtained using an IonOptix system at 36±1ᵒ C. Myocytes were paced at 0.5, 1, 2, 3, and 4 Hz. We found that exposure to βOHB had no effect on excitation-contraction coupling. However, culturing cells with βOHB results in a significant increase in both contraction and calcium in RPMI 1640 media. Dose response experiments demonstrated 0.5 mM βOHB is enough to increase myocyte contraction in the absence of glucose. However, βOHB has no measurable effects on myocytes cultured in a nutrient rich media, M199, HEPES. Therefore, βOHB improves single cell excitation-contraction coupling, is protective against hypoxia, and may be a beneficial adaptation for the heart during periods of nutrient scarcity and or metabolic dysregulation.
Keywords: Excitation-contraction coupling; Hypoxia; Ketone body; β-Hydroxybutyrate.
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