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has been demonstrated to make important improvements in skeletal muscle function,
glucose homeostasis, respiratory muscle strength, locomotor coordination, bone sta-
bility and psychological well-being among many others findings. The intensity-
controlled treadmill exercise in adult rats produces improved cardiac function and
increased myocardial mass through cardiomyocyte hypertrophy as well as new car-
diomyocyte and capillary formation. In models of systolic heart failure, endurance
training has been shown to promote the reversal of remodeling accompanied by
marked improvements in both systolic and diastolic left ventricle functions as well
as decreases in diameters measured at the of end of diastole. The reversal of the
negative remodeling is attributed to the effects of endurance exercise These exercise-
induced improvements include reductions in cardiomyocyte apoptosis and cardiac
fibrosis, increases in phosphoinositide 3-kinase (PI3K) activity, improvements in the
cardiac handling of calcium, improvements in endothelial function resulting from
increases in nitric oxide (NO) production, increases in parasympathetic tone and
marked improvements in the antioxidative protection mechanisms of the cardiac
muscle [ 38 – 40 ]. Reductions in cardiomyocyte apoptosis can be explained by the
activation and subsequent differentiation of cardiac stem cells and progenitors [ 43 ].
The signaling cascade most often characterized as mediating physiological cardiac
growth is the insulin-like growth factor-1 (IGF-1)-PI3K(p110α)-Akt pathway. The
activity of this pathway and ensuing downstream phosphorylation of Akt substrates
were increased in the hypertrophic hearts of transgenic mice overexpressing the
IGF-1 receptor (IGF-1R). Akt, (also known as protein kinase B), is a well-character-
ized serine/threonine kinase that is targeted by PI3K. Of the three Akt isoforms,
Akt1 and Akt2 are expressed at high levels in cardiac tissue [ 45 – 47 ]. Moreover, in
mice that had undergone endurance swim training, cardiomyocyte hypertrophy and
renewal were observed. These beneficial changes were dependent on decreased
expression of the transcription factor CCAAT/enhancer-binding protein beta
(CEBPβ). Interestingly, expression of Akt that was specifically targeted to the
nucleus of cardiac tissue of transgenic mice resulted in prolonged cycling of postna-
tal cardiomyocytes and expansion of the c-kitpos-Nkx-2.5pos cardiac progenitor cell
population [ 44 ].
Clearly, animal models have provided researchers with solid evidence that sup-ports a direct link between the beneficial effects of training and intracellular signal-
ing pathways responsible for hypertrophy and fibrosis in the heart. At the molecular
level, recent studies in animals have suggested that activation of the PI3K (p110)
pathway could be implicated in exercise-induced cardioprotection. In one study,
levels of interstitial fibrosis were significantly reduced thereby improving survival
by approximately 20% [ 41 ]. In a rat model of ischemic heart failure, exercise train-
ing resulted in a marked decrease in the expression of angiotensin-converting
enzyme mRNA as well as angiotensin II-1 receptors (AT1) in myocardial tissue
after a 2 month training regimen with a treadmill. Given that almost all of the angio-
tensin II found in the heart (>90%) is produced locally within the cardiac muscle,
this particularly important finding implies that angiotensin II levels are significantly
reduced locally, in the heart, as a consequence of exercise training. This local
decrease in angiotensin II activity also results in decreased fibrosis. The evidence
J. Kyselovič and J.J. Leddy