The study reports that in diabetic myocardium, a reduced and metabolically less heterogeneous C6 contractile cardiomyocyte subtype and TXNIP/PDK4-mediated metabolic reprogramming underlie vulnerability to ischemia-reperfusion injury, and that regulating TXNIP/PDK4 to optimize myocardial energy metabolism improves this vulnerability and protects the myocardium.
Single-cell sequencing identified a cardiomyocyte subtype, C6, characterized by myocardial contraction.
A reduced number of C6 cardiomyocytes, together with reduced metabolic heterogeneity, is proposed as the basis of myocardial ischemia-reperfusion injury in diabetes.
TXNIP/PDK4-mediated metabolic reprogramming, a hyperdependence on fatty-acid oxidation, is identified as an important reason for increased myocardial vulnerability in diabetes.
Regulating TXNIP/PDK4 to optimize myocardial energy metabolism improved the vulnerability of the diabetic myocardium and provided myocardial protection.
The study was motivated by a high prevalence of adverse cardiac events in diabetic patients undergoing perioperative ischemia-reperfusion injury, with unknown mechanisms.
People with diabetes are more likely to have heart problems when blood flow to the heart is interrupted and then restored, as can happen around surgery. This is called ischemia-reperfusion injury. Why the diabetic heart is so vulnerable has not been clear. This study used single-cell sequencing, tissue staining, metabolic profiling, and animal experiments to look for an explanation. The researchers identified a type of heart muscle cell, called C6, that is involved in contraction. In diabetes, they report that there are fewer of these cells and that they show less metabolic variety, which they propose underlies the heart's vulnerability to this injury. They also found that a pathway involving the proteins TXNIP and PDK4 pushes heart cells into an over-reliance on burning fatty acids for energy, which makes the diabetic heart more susceptible to damage. In animal experiments, adjusting TXNIP/PDK4 to improve how the heart cells produce energy made the diabetic heart less vulnerable and protected it. This research suggests that targeting heart energy metabolism could be a future way to protect diabetic hearts, but the work is at an early stage. The abstract reports only animal and laboratory findings, so it is unknown whether the approach would work in people.
Zeng Z, Shi W, He Y, Wang Y, Pu C, Tan J, et al.. (2026). Txnip/PDK4-Mediated Hyperdependence on Fatty-Acid Oxidation Amplifies Susceptibility of Diabetic Myocardium to Ischemia-Reperfusion Damage.. Journal of diabetes. https://doi.org/10.1111/1753-0407.70277