, a homolog of the Irisin precursor , is critical for exercise performance and cardiac autophagy.

Mammalian encodes a protein precursor of Irisin, which is important for exercise-dependent regulation of whole-body metabolism. In a genetic screen in , we identified (), which shows substantial protein homology to mouse and human , as a regulator of autophagy acting downstream of Atg1/Atg13. Physiologically, -deficient flies showed reduced exercise performance and defective cold resistance, which were rescued by exogenous expression of . Exercise training increased endurance in wild-type flies, but not in -deficient flies. Conversely, Idit is induced upon exercise training, and transgenic expression of in wild-type flies increased endurance to the level of exercise trained flies. Finally, 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 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.