Exercise Modulates miR-276a/nej Expression and Function in the Drosophila Heart: A Possible Contribution of the Fat...

Cardiac rhythm and pumping function are essential outputs of cardiac homeostasis and depend on precise molecular regulation. The histone acetyltransferases CBP/p300 have been implicated in cardiac remodeling and functional regulation. nej, the Drosophila homolog of CBP/p300, may therefore represent an important regulator of cardiac function. However, the relationship between miR-276a and nej in the heart, as well as the potential involvement of the fat body in this regulatory relationship, remains unclear. Using Drosophila as a model, we first examined the effects of cardiac-specific nej overexpression and knockdown on cardiac function and tested the interaction between miR-276a and the nej 3' untranslated region using a dual-luciferase reporter assay. We subsequently manipulated miR-276a using Hand-Gal4 and Cg-Gal4 and assessed miR-276a and nej expression in cardiac samples, cardiac function, and climbing ability. Finally, we investigated the effects of an exercise intervention on cardiac miR-276a/nej expression and functional outcomes. Both cardiac-specific overexpression and knockdown of nej impaired cardiac rhythm, reduced pumping function, and decreased climbing ability. The reporter assay supported a functional interaction between miR-276a and the nej 3' untranslated region, while cardiac-specific miR-276a manipulation was accompanied by inverse changes in nej mRNA expression and by cardiac and climbing abnormalities. Cg-Gal4-mediated miR-276a upregulation or downregulation was associated with altered miR-276a and nej expression in cardiac samples and with cardiac and climbing impairments. Exercise improved cardiac and climbing ability in both cardiac miR-276a knockdown and overexpression groups. It increased cardiac miR-276a expression and decreased nej expression in the cardiac knockdown group but did not significantly alter either transcript in the cardiac overexpression group. Exercise also improved cardiac function in both Cg-Gal4-mediated miR-276a knockdown and overexpression groups. In the Cg-Gal4-mediated knockdown group, this improvement was accompanied by increased miR-276a and decreased nej expression in cardiac samples. These findings indicate that exercise modulates cardiac function and miR-276a/nej expression in a context-dependent manner and suggests a possible contribution of the fat body.