Regular treadmill exercise restores cardioprotective signaling pathways in obese mice independently from improvement in associated co-morbidities

Abstract

Obesity is a major health issue that impedes the ability of preconditioning and postconditioning to protect the myocardium against infarction secondary to dysregulation of kinase signalling pathways. Moreover, exercise decreases cardiovascular mortality in obese patients but the mechanism remains to be established. Wild-type (WT) and obese (ob/ob) mice were assigned to sedentary conditions or regular treadmill exercise (1h/day, 5 days/7, 4 weeks, 4° slope, 10-30 cm/s) and underwent 30 min of coronary artery occlusion followed by 24 h of reperfusion for infarct size measurement. In WT, exercise reduced infarct size by 60% and increased phosphorylation of kinases such as Akt, ERK 1/2, p70S6K, AMPK and GSK31. Importantly, the level of corresponding phosphatases PTEN, MKP-3 and PP2C was decreased. Calcium concentration inducing opening of mitochondrial permeability transition pore (mPTP) was increased by exercise. In ob/ob, regular exercise induced a robust cardioprotection by reducing infarct size (-67%), increasing kinase phosphorylation, decreasing phosphatase levels and improving the resistance to mPTP opening. However exercise did not modify hyperglycemia, hypercholesterolemia, hyperinsulinemia, fat mass and body weight in obese mice. In conclusion, regular exercise induces cardioprotection against myocardial infarction despite obesity and restores pro-survival signalling pathways with simultaneous increase in kinase phosphorylations, decreased levels of phosphatases and increased resistance of mPTP opening, independently from improvement in associated comorbidities.

Exercise training promotes cardioprotection through oxygen-sparing action in high fat-fed mice

“…In a type 1 diabetic model, Broderick et al (7) have reported that 10 wk of continuous, moderate-intensity, treadmill running improved postischemic function in isolated perfused rat hearts subjected to ischemia-reperfusion. In a recent report by Pons and colleagues (37), decreased infarct size following treadmill running was demonstrated in a genetic model of severe obesity (ob/ob) mice that underwent in situ coronary artery occlusion followed by 24 h of reperfusion. However, it should be noted that this was an in vivo study using a model of genetic obesity lacking the gene encoding for leptin, a hormone shown to be proinflammatory and plays a role in the regulation of immunity (26,47).…”

“…Although exercise has been reported to induce cardioprotection and improve ischemic tolerance in nondiabetic hearts through a range of molecular mechanisms (18,38), studies in diabetic and/or obese animal models are few (7,37). In a type 1 diabetic model, Broderick et al (7) have reported that 10 wk of continuous, moderate-intensity, treadmill running improved postischemic function in isolated perfused rat hearts subjected to ischemia-reperfusion.…”

Interaction of Risk Factors, Comorbidities, and Comedications with Ischemia/Reperfusion Injury and Cardioprotection by Preconditioning, Postconditioning, and Remote Conditioning

“…However, one can speculate that the comorbidity may interfere with cardioprotection by modulating mitochondrial function. An interesting study by Pons et al (2013) showed that regular treadmill exercise was able to protect the heart in obese (ob/ob) mice through the activation of prosurvival kinases (Akt, ERK1/2, GSK-3b, p70S6 kinase, AMPK) and in the absence of any improvement in metabolic profile. These findings suggest that regular exercise may have beneficial effects on the heart independently of any effect it may have on the metabolic profile.…”

The Role of MicroRNAs in the Cardiac Response to Exercise

“…Similarly, Akt1 appears to be the PI3K effector that is both necessary and sufficient for physiological hypertrophy while actually inhibiting pathological hypertrophy induced by pressure overload (DeBosch et al 2006). Conversely, levels of the phosphatase and tensin homolog (PTEN), which inhibits PI3K/Akt signaling, decrease in the heart in response to exercise (Ma et al 2013;Pons et al 2013). We found that increased Akt1 expression in cardiomyocytes causes a decrease in expression of the transcription factor C/EBPb, and mice heterozygous for C/EBPb deletion recapitulate many of the cardiac phenotypes seen with exercise and are resistant to pressure-overload-induced cardiac dysfunction (Bostrom et al 2010).…”