Dissecting the molecular landscape of exercise-mediated protection against fructose-induced cardiac dysfunction:...

Excessive fructose consumption, mainly driven by industrial sweeteners, combined with increasingly sedentary lifestyles, has contributed substantially to the global rise in cardiometabolic diseases. Although the evolutionary balance between fructose intake and energy expenditure has been disrupted, it may be restored through targeted lifestyle interventions. This review examines the cardioprotective potential of physical exercise in the context of high fructose intake. Owing to the limited number of human studies, we analyzed 30 animal studies identified in PubMed, focusing on underlying cellular and molecular mechanisms and their possible relevance to lifestyle interventions in humans with impaired cardiometabolic health. Regarding fructose metabolism, exercise has been observed to reduce intestinal fructose absorption, increase hepatic fructose oxidation, suppress fructose-stimulated de novo lipogenesis, and decrease serum uric acid level, thereby attenuating the harmful effects of fructose on the heart. Consistent with these metabolic adaptations, across diverse exercise protocols in trained fructose-fed animals, consistent improvements in myocardial structure, diastolic function, cardiac electrical stability, neurohumoral regulation, and coronary blood flow were observed. These beneficial effects are associated with exercise-induced modulation of key pathways involved in oxidative stress, inflammation, energy substrate metabolism, mitochondrial biogenesis, insulin signaling, cardiac renin-angiotensin system, and nitric oxide synthesis. Notably, these benefits are observed predominantly with low-to moderate-intensity aerobic exercise, although high-intensity interval training is also worth considering. Collectively, the available evidence supports exercise as a promising non-pharmacological strategy for counteracting excessive fructose consumption-induced cardiac dysfunction and underscores the need for well-designed studies in human populations.