Correction: Impaired Transcriptional Activity of Nrf2 in Age-Related Myocardial Oxidative Stress Is Reversible by Moderate Exercise Training

Abstract

Aging promotes accumulation of reactive oxygen/nitrogen species (ROS/RNS) in cardiomyocytes, which leads to contractile dysfunction and cardiac abnormalities. These changes may contribute to increased cardiovascular disease in the elderly. Inducible antioxidant pathways are regulated by nuclear erythroid 2 p45-related factor 2 (Nrf2) through antioxidant response cis-elements (AREs) and are impaired in the aging heart. Whereas acute exercise stress (AES) activates Nrf2 signaling and promotes myocardial antioxidant function in young mice (,2 months), aging mouse (.23 months) hearts exhibit significant oxidative stress as compared to those of the young. The purpose of this study was to investigate agedependent regulation of Nrf2-antioxidant mechanisms and redox homeostasis in mouse hearts and the impact of exercise. Old mice were highly susceptible to oxidative stress following high endurance exercise stress (EES), but demonstrated increased adaptive redox homeostasis after moderate exercise training (MET; 10m/min, for 45 min/day) for ,6 weeks. Following EES, transcription and protein levels for most of the ARE-antioxidants were increased in young mice but their induction was blunted in aging mice. In contrast, 6-weeks of chronic MET promoted nuclear levels of Nrf2 along with its target antioxidants in the aging heart to near normal levels as seen in young mice. These observations suggest that enhancing Nrf2 function and endogenous cytoprotective mechanisms by MET, may combat age-induced ROS/RNS and protect the myocardium from oxidative stress diseases.

Chronic Endurance Exercise Impairs Cardiac Structure and Function in Middle-Aged Mice with Impaired Nrf2 Signaling

“…Numerous studies have reported that Nrf2 is a master transcriptional factor of antioxidant genes, regulating antioxidant gene expression through their antioxidant response element ARE binding sites (Gounder et al, 2012; Muthusamy et al, 2012; Pall and Levine, 2015). We and others have reported that aging decreases Nrf2 (Safdar et al, 2010; Gounder et al, 2012; Done et al, 2016) and thus to determine whether chronic endurance training exacerbates the age-associated alterations in antioxidant gene expression in the absence of Nrf2, we performed real time PCR analysis for the common Nrf2 target antioxidant gene expression in the aged WT and Nrf2 −/− mouse hearts.…”

“…We and others have reported that aging decreases Nrf2 (Safdar et al, 2010; Gounder et al, 2012; Done et al, 2016) and thus to determine whether chronic endurance training exacerbates the age-associated alterations in antioxidant gene expression in the absence of Nrf2, we performed real time PCR analysis for the common Nrf2 target antioxidant gene expression in the aged WT and Nrf2 −/− mouse hearts. Under sedentary conditions, Nrf2 deficiency resulted in a significant decrease in the expression of Nqo1, Gclm, Ho-1, Sod1, Gst- α in Nrf2 −/− mice in relation to aged WT mice.…”

“…Earlier we reported that acute endurance exercise (2 days) evoked antioxidant cytoprotection in young WT animals whereas Nrf2 −/− young mice and aged WT mice that is intrinsically defective in Nrf2 signaling did not receive similar benefits as that of young WT (Gounder et al, 2012; Muthusamy et al, 2012). Moreover, we have demonstrated that moderate exercise regimens are found to be cardio-protective via priming the Nrf2-dependent antioxidant signaling and maintaining myocardial defense in WT animals (Gounder et al, 2012).…”

“…Moreover, we have demonstrated that moderate exercise regimens are found to be cardio-protective via priming the Nrf2-dependent antioxidant signaling and maintaining myocardial defense in WT animals (Gounder et al, 2012). Notably, longitudinal human and several animal studies have shown that age-associated cardiac function fall into two categories such as pathological (accumulated and/or forced changes over time) and normal (gradual deterioration) (Lakatta and Levy, 2003a,b; Dai and Rabinovitch, 2009; Pandey et al, 2017).…”

Antioxidant and Adaptative Response Mediated by Nrf2 during Physical Exercise

“…Likewise, in general, an active lifestyle has been related to physiological, metabolic, and transcriptional changes that support the prevention of chronic diseases such as diabetes, as well as preventing or delaying muscle-mass atrophy caused by aging [33]. In another sense, it has been observed that acute exhaustive training dramatically increases the production of free radicals [34]. Vigorous exercise has been demonstrated to occasionally cause sudden cardiac death in sedentary individuals with prior cardiovascular disease, but this is not the case with the habitual practice of moderate exercise [35].…”