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

• Published in: International journal of molecular sciences Vol. 23; no. 18; p. 10840
• Main Authors: Barau, Caroline, Leick, Shirin, Caccia, Claudio, Portal, Lolita, Leoni, Valerio, Le Corvoisier, Philippe, Morin, Didier, Ghaleh, Bijan, Pons, Sandrine
• Format: Journal Article
• Language: English
• Published: Switzerland MDPI AG 16.09.2022; MDPI
• Subjects: Animals; Apoptosis; Biomarkers; Calcium - metabolism; Cardiomyocytes; Endocrinology and metabolism; Heart attacks; Human health and pathology; Humans; Investigations; Ischemia; Kinases; Life Sciences; Mice; Mice, Obese; Mitochondria; Mitochondria, Heart - metabolism; Mitochondrial Membrane Transport Proteins - metabolism; Mitochondrial Permeability Transition Pore; Musculoskeletal system; Myocardial Reperfusion Injury - metabolism; Obesity; Obesity - metabolism; Oxysterols - metabolism; Phosphatase; Phosphorylation; Protein Kinase C-epsilon - metabolism; Proteins; Proto-Oncogene Proteins c-akt - metabolism; Signal Transduction - physiology; Tissues and Organs; pro-survival kinases; protein phosphatases; regular exercise; oxysterols; mitochondrial permeability transition pore; obesity
• ISSN: 1422-0067; 1661-6596; 1422-0067
• DOI: 10.3390/ijms231810840

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 7β-hydroxycholesterol (7βOH) 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 7βOH concentration was reduced. Moreover, exercise induced the translocation of PKCε 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 7βOH concentration was consistent with observations made in mice. In conclusion, regular exercise enhanced the RISK pathway by increasing kinase phosphorylation and PKCε translocation and decreasing 7βOH 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 7βOH as a candidate marker for evaluating cardiovascular risk factors in obesity.