220
vasculature- protecting effects of exercise are mediated, at least in part, through sup-
pression of glycation. Another study conducted by Santilli et al. [ 162 ] showed the
beneficial effects of regular high-intensity exercise training on platelet activation
markers, lipid peroxidation and AGE/RAGE axis. Therefore, further studies are
required to highlight the effects of exercise training on the AGE/RAGE axis in
DCM.
7 Exercise Increases Myocardial Antioxidant Capacity
Impairment of antioxidant defenses is a feature of the diabetic myocardium; there-
fore, enhancement of the antioxidant system in the heart could exert beneficial
effect against DCM. In this context, exercise training has been reported to up-
regulate gene and protein expression of the antioxidant defenses in the heart of
diabetic and obese animal models [ 33 , 163 ]. The study of Bo et al. [ 124 ] showed
increased expression and activity of myocardial MnSOD in response to acute exer-
cise. A recent study showed increased cardiac SOD-2 and catalase expression in
response to swimming training in ovariectomized rats [ 164 ]. Hyatt et al. [ 165 ] dem-
onstrated increased protein levels of SOD-2 in the heart of Sprague-Dawley rats
following endurance exercise training. In addition, exercise reduced lipid peroxida-
tion and increased the abundance of antioxidant defenses in cardiac tissues of
hypertensive ovariectomized rats undergoing fructose overload [ 166 ].
The mechanism behind the beneficial effect of exercise on the myocardium anti-oxidant defenses involves up-regulation of the transcription factor nuclear factor
erythroid 2-related factor 2 (Nrf2), a master regulator of cellular antioxidants
(Fig. 12.6). Tan et al. [ 167 ] reported exercise-induced increase in insulin sensitivity
and subsequently Nrf2 activity through the PI3K pathway in myocardial cells both
in vivo and in vitro. To mimic acute exercise, Horie et al. [ 168 ] applied electrical
pulse stimulation (EPS) in C2CL2 myotubes and showed that the increased expres-
sion of Nrf2 and its related antioxidant genes was correlated to intensity and dura-
tion of the stimulus. Interestingly, this induced antioxidant gene expression was
blunted in response to Nrf2 knockdown. Moreover, mice showed increased Nrf2
gene [ 169 , 170 ] and protein expression [ 170 ], and Nrf2-dependent phase II enzymes
[ 169 , 171 ] following a single bout of acute exercise. Accordingly, exercise up-
regulated Nrf2 signaling in mouse myocardium as demonstrated in different studies
[ 125 , 172 ]. Furthermore, Muthusamy et al. [ 125 ] reported increased nuclear accu-
mulation of Nrf2 and expression of phase II antioxidants in response to exercise in
the myocardium of wild-type mice when compared with Nrf2−/− mice. These data
highlight that exercise exerts its benefits through activation of Nrf2 signaling.
However, more studies are needed to explore the possible role of exercise on Nrf2
signaling in the diabetic myocardium.
A.M. Mahmoud