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8 Endurance Exercise Impairs Nrf2-Antioxidant Signaling
in the Aging Heart
The strategy of endurance exercise has been proposed to mitigate the onset of sar-
copenia with age [ 174 ] and sustain the mitochondrial function in aging and related
comorbidities [ 175 ]. In addition, endurance training has been shown to exert anti-
inflammatory effects, increase insulin sensitivity and counteracts the loss of skeletal
muscle mass and strength [ 176 – 179 ]. Although, endurance exercise is considered to
be a feasible and effective method in older adults [ 180 – 182 ], a continued elevation
of oxidative damage of proteins associated with an inability to improve skeletal
muscle and mitochondrial protein quality is seen in older people after 8 weeks of
endurance training aging [ 183 ]. Further, a randomized, single-blinded clinical trial
demonstrated that endurance exercise was either ‘neutral’ or ‘negative’ with an
unaltered rate of oxygen consumption (VO 2 ), left ventricular (LV) structure and
function [ 184 , 185 ]. Given the inconsistent effects of endurance training besides the
duration and intensity of exercise regimen, we also observed that endurance exer-
cise can evoke stress that leads to a hyper-oxidative condition in the heart of aged
mice [ 75 ]. When the young-adult (~6 months old) mice were stressed to their endur-
ance capacity, an activation of Nrf2 signaling along with augmented myocardial
antioxidant response was detected. In contrast, the old mice exhibited a significant
decline in Nrf2 and downregulation of its target genes after EES [ 75 ]. In particular,
the Nrf2 targets such as Nqo1 and Ho1 along with the genes encoding the subunits
of γ-glutamyl cysteine ligase (Gcl – Gclm and Gclc), the rate-limiting enzyme for
GSH biosynthesis, were significantly decreased in the heart of aging when com-
pared to young mice following EES. Gene expression levels for the ROS scavenging
enzymes such as Sod2, catalase and Gpx1 were also blunted in the old mice.
Induction of mRNA levels for G6PD and GSR, key enzymes responsible for recy-
cling oxidized glutathione (GSSG) back into its reduced form (GSH), revealed a
parallel trend, being increased in young, but blunted in old mice following
EES. Comparable protein levels of antioxidant enzymes correlated with their tran-
script levels indicating a tight regulation of Nrf2 signaling, which is diminished in
the aging heart after EES. These results indicate that aged hearts were unable to
combat EES-induced oxidative stress and hence become susceptible to pathological
remodeling. Further, our data using genetically modified Nrf2 mice indicate that a
loss of Nrf2 signaling could have detrimental effects besides antioxidant regulation
in that it might either directly or indirectly be involved in pathological remodeling
of myocardial structure and functional disintegration of the heart in response to
intense endurance exercise training (Figs. 13.3 and 13.4). This denotes that a dis-
crete Nrf2 gene content (either presence or absence) might significantly influence
the outcome of the endurance training. Consequently, these findings from our labo-
ratory underscores that there might be persisting effects and/or burden of age on
Nrf2 dependent redox mechanisms in the heart that can increase cardiovascular
disease risk upon endurance training thereby affecting the quality of life, despite the
13 Cardiac Agingfi– Bene ts offiExercise, Nrf2 Activation andfiAntioxidant Signaling