<i>Iditarod</i>, a <i>Drosophila</i> homolog of the Irisin precursor <i>FNDC5</i>, is critical for exercise performance and cardiac autophagy.

Abstract

Mammalian <i>FNDC5</i> encodes a protein precursor of Irisin, which is important for exercise-dependent regulation of whole-body metabolism. In a genetic screen in <i>Drosophila</i>, we identified <i>Iditarod</i> (<i>Idit</i>), which shows substantial protein homology to mouse and human <i>FNDC5</i>, as a regulator of autophagy acting downstream of Atg1/Atg13. Physiologically, <i>Idit</i>-deficient flies showed reduced exercise performance and defective cold resistance, which were rescued by exogenous expression of <i>Idit</i>. Exercise training increased endurance in wild-type flies, but not in <i>Idit</i>-deficient flies. Conversely, Idit is induced upon exercise training, and transgenic expression of <i>Idit</i> in wild-type flies increased endurance to the level of exercise trained flies. Finally, <i>Idit</i> deficiency prevented both exercise-induced increase in cardiac Atg8 and exercise-induced cardiac stress resistance, suggesting that cardiac autophagy may be an additional mechanism by which <i>Idit</i> is involved in the adaptive response to exercise. Our work suggests an ancient role of an Iditarod/Irisin/FNDC5 family of proteins in autophagy, exercise physiology, and cold adaptation, conserved throughout metazoan species.