The Drosophila model is well
The Drosophila model is well-suited to study the effects of exercise on heart function in a controlled manner. Because flies have an innate reaction to climb up in response to a negative geotaxis stimulus, they can easily be subjected to an exercise routine on a large scale . Evidence supports the idea that regulated exercise training prevents age-related heart dysfunction in flies and has beneficial effects similar to those from aerobic exercise in humans [29,, , ]. A pacing protocol developed for Drosophila allows for the study of cardiac performance in response to increasing the normal heart rate through external electrical field stimulation [135,136]. This is comparable to an exercise stress test used to evaluate the 2NBDG of the human heart [10,136,227]. As flies age, they normally exhibit an increase in cardiac-arrest rate after external electrical pacing, a measurement of heart failure, and a decrease in arrest recovery . However, in exercise-trained elderly flies, a decrease in cardiac-arrest rate and increase in recovery compared to same-age unexercised flies was observed . These findings suggest a beneficial effect of exercise on the Drosophila aging heart. A line of flies selectively bred for increased longevity demonstrated similar cardioprotection accompanied by improved mitochondrial efficiency . Interestingly, such longevity-bred flies as well as three-week-old exercised flies have overlapping changes in whole-body transcript levels, including those for gustatory receptors and genes involved in carbohydrate metabolism, xenobiotic/drug metabolism, and folate biosynthesis . Of note, the extension in lifespan observed upon CR was significantly reduced when flies undergoing CR were allowed to smell, but not to eat, yeast . In line with these results, null mutant flies for the odorant and gustatory receptors Or83b and Gr64a, exhibited improved cardiac stress tolerance in a similar manner to ubiquitous knockdown of the G-protein coupled receptor Mthl3 . The authors suggested that reducing flies' sensory perception of food can enhance exercise capacity, improve cardiac aging, and increase longevity in a manner similar to CR . Indeed, experimental evidence suggests that the beneficial effects of exercise are mediated by octopaminergic activity . Sirt1 (dSir2 in Drosophila) is a NAD+-dependent histone deacetylase, which functions as an energy status sensor and has been implicated in longevity, obesity, and cancer . Upon increased energy demand, when NAD+ levels are highest, Sirt1 deacetylates PGC-1α, producing NADH in the process. This deacetylation activates PGC-1α and in turn induces the transcription of genes involved in gluconeogenesis, glycolysis, and fatty-acid oxidation in a tissue-specific manner . Exercise is known to increase mitochondrial activity [29,250,251] and, more specifically, improve cardiac mitochondrial biogenesis by activating PGC-1α . PGC-1 heterozygous mutant flies exhibited cardiac dysfunction remarkably similar to that observed in HFD-fed control flies . Interestingly, another mutant line for PGC-1, srl, was reported to have delayed development and reduced lifespan . Moreover, overexpression of PGC-1 in adult muscles, including the cardiac tube, protects against heart failure in response to electrical pacing . This protection was increased when PGC-1-overexpressing flies were subjected to exercise training, suggesting that PGC-1 and exercise both have cardioprotective roles . However, cardioprotection achieved by exercise and PGC-1 overexpression may also be mediated by a reduction in triglyceride accumulation [30,144]. In fact, knockdown of dSir2 in the fat body led to a significant increase in total triglyceride levels and free fatty acids . In line with these data, whole-fly dSir2 transcript levels were found to be reduced with age but elevated upon exercise . Microarray data revealed the expression of dSir2 was not changed in the Drosophila heart with age. However, expression of sirt2, which has high identity to human SIRT2 and SIRT3, was found to be significantly decreased . The direct effect of dSir2 overexpression on heart function and cardiac aging remains to be determined. Overall, research in Drosophila has shown that exercise ameliorates heart function decline [29,244,245] and prolongs healthspan [144,244], as similarly demonstrated in vertebrate models .