Sugar or fat: The metabolic choice of the trained heart.

Mammals respond to muscular exercise by increasing cardiac output to meet the increased demand for oxygen in the working muscles and it is well-established that regular bouts of exercise results in myocardial remodeling. Depending on exercise type, intensity and duration, these cardiac adaptations lead to changes in the energetic substrates required to sustain cardiac contractility. In contrast to the failing heart, fatty acids are the preferred substrate in the trained heart, though glucose metabolism is also enhanced to support oxidative phosphorylation. The participation of AMPK/eNOS and PPARα/PGC-1α pathways in the regulation of cardiac metabolism is well known but other players also contribute including sirtuins and integrins-mediated outside-in activation of FAK and other kinases. These regulatory players act by up-regulating fatty acid uptake, transport to mitochondria and oxidation, and glucose uptake via GLUT4. This exercise-induced increase in mitochondria metabolic flexibility is important to sustain the energetic demand associated with cardiomyocyte hypertrophy and hyperplasia promoted by IGF-1 and neuregulin-1-induced PI3K/Akt signaling. So, the timeless advice of Hippocrates "walking is the best medicine" seems to be justified by the promotion of mitochondrial health and, consequently, the beneficial metabolic remodeling of the heart.