Individual and combined effects of wheel running and ischemic preconditioning in protecting the rat heart from reperfusion injury

It's well known that exercise-training (TRN) and ischemic preconditioning (IPC) reduce cardiomyocyte (CM) death following ischemia and reperfusion (IR), but it's unknown if protection can be elicited by moderate exercise TRN or if the effects of TRN and IPC summate to generate greater protection than either protocol alone. To address these questions, we utilized wheel running, a moderate intensity paradigm, to TRN male and female rats, and two IPC protocols. Hearts were studied ex vivo with regional ischemia (RI) produced by occluding the left anterior descending coronary artery for 30 min followed by 3 hr reperfusion. IPC consisted of a 5-min period of global ischemia and either 5 (PC5) or 10 (PC10) min reperfusion before the initiation of index RI. We found that wheel running and PC10, but not PC5, reduced CM death compared to sedentary, with the TRN effect greater in males. TRN, but not IPC, showed functional protection by reducing the loss of left ventricular developed pressure. Surprisingly, the TRN and PC10 protection from cell death were not additive, suggesting these modalities converge on the same pathway. We also showed that TRN significantly improved mitochondrial respiration and ΔΨm repolarization during oxidative phosphorylation after IR when compared to SED rats; the improved bioenergetics was associated with the increased pro-survival kinase, hexokinase II (HKII), translocation to mitochondria, which was mediated by increased total Akt and the phosphorylated Akt. We conclude that TRN induced cardioprotection is mediated, in part, by preservation of mitochondrial bioenergetics likely mediated via the Akt-pAkt-HKII signaling pathway.