Cardioprotective Signaling Pathways in Obese Mice Submitted to Regular Exercise: Effect on Oxysterols

Exercise induces cardioprotection against myocardial infarction, despite obesity, by restoring pro-survival pathways and increasing resistance of mitochondrial permeability transition pore (mPTP) opening at reperfusion. Among the mechanisms involved in the inactivation of these pathways, oxysterols appear interesting. Thus, we investigated the influence of regular exercise on the reperfusion injury salvage kinase (RISK) pathway, oxysterols, and mitochondria, in the absence of ischemia-reperfusion. We also studied 7 beta-hydroxycholesterol (7 beta OH) concentration (mass spectrometry) in human lean and obese subjects. Wild-type (WT) and obese (ob/ob) mice were assigned to sedentary conditions or regular treadmill exercise. Exercise significantly increased Akt phosphorylation, whereas 7 beta OH concentration was reduced. Moreover, exercise induced the translocation of PKC epsilon from the cytosol to mitochondria. However, exercise did not affect the calcium concentration required to open mPTP in the mitochondria, neither in WT nor in ob/ob animals. Finally, human plasma 7 beta OH concentration was consistent with observations made in mice. In conclusion, regular exercise enhanced the RISK pathway by increasing kinase phosphorylation and PKC epsilon translocation and decreasing 7 beta OH concentration. This activation needs the combination with stress conditions, i.e., ischemia-reperfusion, in order to inhibit mPTP opening at the onset of reperfusion. The human findings suggest 7 beta OH as a candidate marker for evaluating cardiovascular risk factors in obesity.

Automated summary

Exercise can provide cardioprotection against myocardial infarction by restoring pro-survival pathways and increasing resistance of mitochondrial permeability transition pore. Oxysterols, specifically 7 beta-hydroxycholesterol, play a role in the inactivation of these pathways. Regular exercise enhances the RISK pathway and decreases 7 beta-hydroxycholesterol concentration.