Exercise Mediated Nrf2 Signaling Protects the Myocardium From Isoproterenol-Induced Pathological Remodeling.

Gobinath Shanmugam,Silvio H Litovsky,Anil K Challa,Christopher J Davidson,Baskaran Athmanathan,Prasanna Krishnamurthy,Asokan Devarajan,Namakkal Soorappan Rajasekaran

doi:10.3389/fcvm.2019.00068

Abstract

Although exercise derived activation of Nrf2 signaling augments myocardial antioxidant signaling, the molecular mechanisms underlying the benefits of moderate exercise training (MET) in the heart remain elusive. Here we hypothesized that exercise training stabilizes Nrf2-dependent antioxidant signaling, which then protects the myocardium from isoproterenol-induced damage. The present study assessed the effects of 6 weeks of MET on the Nrf2/antioxidant function, glutathione redox state, and injury in the myocardium of C57/BL6J mice that received isoproterenol (ISO; 50 mg/kg/day for 7 days). ISO administration significantly reduced the Nrf2 promoter activity (p < 0.05) and downregulated the expression of cardiac antioxidant genes (Gclc, Nqo1, Cat, Gsr, and Gst-μ) in the untrained (UNT) mice. Furthermore, increased oxidative stress with severe myocardial injury was evident in UNT+ISO when compared to UNT mice receiving PBS under basal condition. Of note, MET stabilized the Nrf2-promoter activity and upheld the expression of Nrf2-dependent antioxidant genes in animals receiving ISO, and attenuated the oxidative stress-induced myocardial damage. Echocardiography analysis revealed impaired diastolic ventricular function in UNT+ISO mice, but this was partially normalized in the MET animals. Interestingly, while there was a marginal reduction in ubiquitinated proteins in MET mice that received ISO, the pathological signs were attenuated along with near normal cardiac function in response to exercise training. Thus, moderate intensity exercise training conferred protection against ISO-induced myocardial injury by augmentation of Nrf2-antioxidant signaling and attenuation of isoproterenol-induced oxidative stress.

Highlights

Nuclear factor erythroid 2 like 2 (NFE2L2/Nrf2) is the major stress response transcriptional regulator for antioxidant genes
Administration of isoproterenol for 1 week period (7 days) in the UNT mice showed a significant increase in heart weight (HW) to body weight (BW) ratios (HW/BW) compared to the UNT control group
The hematoxylin eosin (H&E) stained images from the UNT mice treated with isoproterenol displayed widespread myocardial necrosis with degeneration and obvious leukocyte infiltration (Figure 1C), whereas the moderate exercise training (MET) mice treated with isoproterenol showed minimal cell death foci and diminished leukocyte infiltration

Summary

Introduction

Nuclear factor erythroid 2 like 2 (NFE2L2/Nrf2) is the major stress response transcriptional regulator for antioxidant genes. Genetic approaches to augment Superoxide Dismutase (SOD, antioxidant enzyme) through transgenic overexpression (11) or targeting transcription factors (i.e., NFE2L2 or NRF2) responsible for antioxidant genes (12) have resulted in their abundance, leading to unusual redox shifts that fail to combat oxidative stress mediated anomalies (13–15). As induction of Nrf2-dependent antioxidant signaling by pharmacological agents was associated with toxic side effects (16–20), a non-pharmacologic approach may be of greater value. With these approaches, we and others have recently reported that sustained physical activity or routine exercise training upregulates Nrf2-dependent cytoprotective targets in human skeletal muscle and mouse heart (21–25). We tested a hypothesis that exercise based stabilization/activation of Nrf[2], and its transcriptional regulation of antioxidants protects the heart from isoproterenol-induced myocardial damage and dysfunction

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